Systems and methods of facilitating therapeutic neuromodulation

ABSTRACT

A method of facilitating therapeutic neuromodulation of a heart of a patient includes positioning an electrode in a pulmonary artery, positioning a sensor in vasculature, delivering via a stimulation system first and second electrical signals of a series of electrical signals to the electrode. The second electrical signal differs from the first electrical signal by a magnitude of a first parameter of a plurality of parameters. The method includes determining, via the sensor, sensor data indicative of one or more heart activity properties in response to the delivery of the series of electrical signals, and delivering a therapeutic neuromodulation signal to the pulmonary artery using selected electrical parameters. The selected electrical parameters include a selected magnitude of the first parameter. The selected magnitude of the first parameter is based at least partially on the sensor data. The therapeutic neuromodulation signal increases heart contractility.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 15/540,161, filed Jun. 27, 2017, which is a national phase of PCTApplication No. PCT/US2016/012082, filed Jan. 4, 2016, which claimspriority benefit of U.S. Provisional Patent App. No. 62/099,834, filedJan. 5, 2015, each of which is hereby incorporated by reference in itsentirety.

BACKGROUND Field

The present disclosure relates generally to methods and systems forfacilitating modulation (e.g., electrical neuromodulation), and moreparticularly to methods and systems for facilitating therapeutic andcalibration electrical neuromodulation of one or more nerves in andaround the heart.

Description of the Related Art

Acute heart failure is a cardiac condition in which a problem with thestructure or function of the heart impairs its ability to supplysufficient blood flow to meet the body's needs. The condition impairsquality of life and is a leading cause of hospitalizations and mortalityin the western world. Treating acute heart failure is typically aimed atremoval of precipitating causes, prevention of deterioration in cardiacfunction, and control of the patient's congestive state.

SUMMARY

Treatments for acute heart failure include the use of inotropic agents,such as dopamine and dobutamine. These agents, however, have bothchronotropic and inotropic effects and characteristically increase heartcontractility at the expense of significant increases in oxygenconsumption secondary to elevations in heart rate. As a result, althoughthese inotropic agents increase myocardial contractility and improvehemodynamics, clinical trials have consistently demonstrated excessmortality caused by cardiac arrhythmias and increase in myocardiumconsumption.

As such, there is a need for selectively and locally treating acuteheart failure and otherwise achieving hemodynamic control withoutcausing unwanted systemic effects. Accordingly, in some embodiments, noinotropics are used. In other embodiments, reduced dosages of inotropicsmay be used because, for example, synergistic effects are providedthrough various embodiments herein. By reducing the dosages, the sideeffects can also be significantly reduced.

Several embodiments of the present disclosure provide for methods oftissue modulation, such as neuromodulation, for cardiac and otherdisorders. For example, some embodiments provide methods and devices forneuromodulation of one or more nerves in and around a heart of apatient. Several methods of the present disclosure, for example, may beuseful in electrical neuromodulation of patients with cardiac disease,such as patients with acute or chronic cardiac disease. Several methodsof the present disclosure encompass, for example, neuromodulation of oneor more target sites of the autonomic nervous system of the heart, wheresensed non-electrical heart activity properties are used in makingadjustments to one or more properties of the electrical pulses deliveredto the patient. Non-limiting examples of medical conditions that can betreated according to the present disclosure include cardiovascularmedical conditions.

Several methods of the present disclosure allow for electricalneuromodulation of the heart of the patient, for example includingdelivering one or more electrical pulses through a catheter positionedin a pulmonary artery of the heart of the patient, sensing from at leasta first sensor positioned at a first location within the vasculature ofthe heart one or more heart activity properties (e.g., a non-electricalheart activity property) in response to the one or more electricalpulses, and adjusting a property of the one or more electrical pulsesdelivered through the catheter positioned in the pulmonary artery of theheart in response to the one or more heart activity properties. Themethods may provide adjuvant cardiac therapy to the patient.

Sensing from at least the first sensor positioned at the first locationcan include sensing one or more of a pressure property, an accelerationproperty, an acoustic property, a temperature, and a blood chemistryproperty from within the vasculature of the heart. Among otherlocations, the first sensor can be positioned in one of a left pulmonaryartery, a right pulmonary artery, a pulmonary artery branch vessel, or apulmonary trunk of the heart. The one or more electrical pulses canoptionally be delivered through the catheter positioned in one of theleft pulmonary artery, the right pulmonary artery, or pulmonary trunk ofthe heart that does not contain the first sensor. The first sensor canalso be positioned in a pulmonary trunk of the heart.

Other locations for the first sensor can include in the right ventricleof the heart and in the right atrium of the heart. When positioned inthe right atrium of the heart, the first sensor can optionally bepositioned on the septal wall of the right atrium of the heart. Thefirst sensor could also be positioned on the septal wall of the rightventricle. The right ventricle and the left ventricle share a septalwall, so a sensor in the right ventricle or on the septal wall of theright ventricle may be preferable for detecting properties indicative ofleft ventricle contractility or cardiac output. Additional locations forpositioning the first sensor include in a superior vena cava of theheart, the inferior vena cava of the heart, and in a coronary sinus ofthe heart. When positioned in the coronary sinus of the heart, the firstsensor can be used to sense at least one of a temperature or a bloodoxygen level.

In some embodiments, the first sensor may be positioned in the leftatrium (e.g., by forming an aperture in the septal wall between theright atrium and the left atrium, or by using a patent foramen ovale(PFO) or atrial septal defect (ASD)). A sensor in the left atrium may beuseful for detecting properties indicative of the left ventricle. If theleft atrium has been accessed, in some embodiments, the sensor may bepositioned in the left ventricle itself, which may provide the mostdirect measurement of properties associated with the left ventricle. Insome embodiments, the sensor may be positioned downstream of the leftventricle, including the aorta, aortic branch arteries, etc. When theprocedure is complete, any aperture that was created or existing may beclosed using a closure device such as Amplatzer, Helex, CardioSEAL, orothers.

Some methods can include sensing one or more cardiac properties from askin surface of the patient, and adjusting the property of the one ormore electrical pulses delivered through the catheter positioned in thepulmonary artery of the heart in response to the one or more heartactivity properties (e.g., non-electrical properties) from the firstsensor positioned at a first location within the vasculature of theheart and/or the one or more cardiac properties from the skin surface ofthe patient. The one or more cardiac properties sensed from the skinsurface of the patient can include, for example, an electrocardiogramproperty.

Some methods can include sensing from at least a second sensorpositioned at a second location within the vasculature of the heart oneor more heart activity properties (e.g., non-electrical heart activityproperties) in response to the one or more electrical pulses, andadjusting the property of the one or more electrical pulses deliveredthrough the catheter positioned in the pulmonary artery of the heart inresponse to the one or more heart activity properties from the firstsensor and/or the one or more heart activity properties from the secondsensor.

Adjusting the property of the one or more electrical pulses can includea variety of responses. For example, adjusting the property of the oneor more electrical pulses can include changing which of an electrode orplurality of electrodes on the catheter is used to deliver the one ormore electrical pulses. For another example, adjusting the property ofthe one or more electrical pulses can include moving the catheter toreposition one or more electrodes of the catheter in the pulmonaryartery of the heart. For yet another example, adjusting the property ofthe one or more electrical pulses can include changing at least one ofan electrode polarity, a pulsing mode, a pulse width, an amplitude, afrequency, a phase, a voltage, a current, a duration, an inter-pulseinterval, a duty cycle, a dwell time, a sequence, a wavelength, and/or awaveform of the one or more electrical pulses.

A hierarchy of electrode configurations can be assigned from which todeliver the one or more electrical pulses. The one or more electricalpulses can be delivered based on the hierarchy of electrodeconfigurations, where the one or more heart activity properties sensedin response to the one or more electrical pulses can be analyzed and anelectrode configuration can be selected to use for delivering the one ormore electrical pulses through the catheter positioned in the pulmonaryartery of a heart of a patient based on the analysis. A hierarchy can beassigned to each property of the one or more electrical pulses deliveredthrough the catheter positioned in the pulmonary artery of the heart,where the one or more electrical pulses are delivered based on thehierarchy of each property. The one or more non-electrical heartactivity properties sensed in response to the one or more electricalpulses are analyzed and an electrode configuration can be selected to beused for delivering the one or more electrical pulses through thecatheter positioned in the pulmonary artery of a heart of a patientbased on the analysis. Analyzing the one or more heart activityproperties can include analyzing a predetermined number of the one ormore heart activity properties.

In some embodiments, a method of facilitating therapeuticneuromodulation of a heart of a patient comprises positioning anelectrode in a pulmonary artery of a heart and positioning a sensor in aright ventricle of the heart. The method further comprises delivering,via a stimulation system, a first series of electrical signals to theelectrode. The first series comprises a first plurality of electricalsignals. Each of the first plurality of electrical signals comprises aplurality of parameters. Each of the first plurality of electricalsignals of the first series only differs from one another by a magnitudeof a first parameter of the plurality of parameters. The method furthercomprises, after delivering the first series of electrical signals tothe electrode, delivering, via the stimulation system, a second seriesof electrical signals to the electrode. The second series comprises asecond plurality of electrical signals. Each of the second plurality ofelectrical signals comprises the plurality of parameters. Each of thesecond plurality of electrical signals of the second series only differsfrom one another by a magnitude of a second parameter of the pluralityof parameters. The second parameter is different than the firstparameter. The method further comprises determining, via the sensor,sensor data indicative of one or more non-electrical heart activityproperties in response to delivering the first series of electricalsignals and the second series of electrical signals, and delivering atherapeutic neuromodulation signal to the pulmonary artery usingselected electrical parameters. The selected electrical parameterscomprise a selected magnitude of the first parameter and a selectedmagnitude of the second parameter. The selected magnitudes of the firstand second parameters are based at least partially on the sensor data.The therapeutic neuromodulation signal increases heart contractilitymore than heart rate.

The method may further comprise delivering, via the stimulation system,a third series of electrical signals to the electrode. The third seriescomprises a third plurality of electrical signals. Each of the thirdplurality of electrical signals comprises the plurality of parameters.Each of the third plurality of electrical signals of the third seriesonly differs from one another by a magnitude of a third parameter of theplurality of parameters. The third parameter is different than the firstparameter and the second parameter. The method may further comprisedetermining, via the sensor, sensor data indicative of the one or morenon-electrical heart activity properties in response to delivering thethird series of electrical signals. The selected electrical parametersmay comprise a selected magnitude of the third parameter. The selectedmagnitude of the third parameter is based at least partially on thesensor data.

The method may further comprise determining a desired hierarchy betweenthe first series and the second series. The pulmonary artery maycomprise a right pulmonary artery. The one or more non-electrical heartactivity properties may comprise at least one of a pressure property, anacceleration property, an acoustic property, a temperature, and a bloodchemistry property. Determining the sensor data may comprisedetermining, via a second sensor on a skin surface, sensor dataindicative of an electrocardiogram property in response to deliveringthe first series of electrical signals and the second series ofelectrical signals.

The first parameter may be one of the following: a polarity, a pulsingmode, a pulse width, an amplitude, a frequency, a phase, a voltage, acurrent, a duration, an inter-pulse interval, a duty cycle, a dwelltime, a sequence, a wavelength, or a waveform, and, optionally, thesecond parameter may be a different one of the following: a polarity, apulsing mode, a pulse width, an amplitude, a frequency, a phase, avoltage, a current, a duration, an inter-pulse interval, a duty cycle, adwell time, a sequence, a wavelength, or a waveform. The secondparameter may be one of the following: a polarity, a pulsing mode, apulse width, an amplitude, a frequency, a phase, a voltage, a current, aduration, an inter-pulse interval, a duty cycle, a dwell time, asequence, a wavelength, or a waveform. The first parameter may comprisecurrent and the second parameter may comprise a parameter relating totiming (e.g., one of frequency and duty cycle).

In some embodiments, a method of facilitating therapeuticneuromodulation of a heart of a patient comprises positioning anelectrode in a pulmonary artery of a heart, positioning a sensor in aright ventricle of the heart, delivering, via a stimulation system, afirst electrical signal of a series of electrical signals to theelectrode, and, after delivering the first electrical signal,delivering, via the stimulation system, a second electrical signal ofthe series of electrical signals to the electrode. The second electricalsignal differs from the first electrical signal by a magnitude of afirst parameter of a plurality of parameters. The method furthercomprises determining, via the sensor, sensor data indicative of one ormore non-electrical heart activity properties in response to thedelivery of the series of electrical signals, and delivering atherapeutic neuromodulation signal to the pulmonary artery usingselected electrical parameters. The selected electrical parameterscomprise a selected magnitude of the first parameter. The selectedmagnitude of the first parameter is based at least partially on thesensor data. The therapeutic neuromodulation signal increases heartcontractility more than heart rate.

The pulmonary artery may comprise a right pulmonary artery. Thepulmonary artery may comprise a left pulmonary artery. The pulmonaryartery may comprise a pulmonary trunk. The one or more non-electricalheart activity properties may comprise at least one of a pressureproperty, an acceleration property, an acoustic property, a temperature,and a blood chemistry property. Determining the sensor data may comprisedetermining, via a second sensor on a skin surface of the patient,sensor data indicative of an electrocardiogram property in response todelivering the series of electrical signals. The first parameter may beone of the following: a polarity, a pulsing mode, a pulse width, anamplitude, a frequency, a phase, a voltage, a current, a duration, aninter-pulse interval, a duty cycle, a dwell time, a sequence, awavelength, or a waveform.

In some embodiments, a method of facilitating therapeuticneuromodulation of a heart of a patient comprises delivering a firstseries of electrical signals to an electrode in a first anatomicallocation, and, after delivering the first series of electrical signalsto the electrode, delivering a second series of electrical signals tothe electrode. The first series comprises a first plurality ofelectrical signals. Each of the first plurality of electrical signalscomprises a plurality of parameters. Each of the first plurality ofelectrical signals of the first series only differs from one another bya magnitude of a first parameter of the plurality of parameters. Thesecond series comprises a second plurality of electrical signals. Eachof the second plurality of electrical signals comprises the plurality ofparameters. Each of the second plurality of electrical signals of thesecond series only differs from one another by a magnitude of a secondparameter of the plurality of parameters. The second parameter isdifferent than the first parameter. The method further comprisessensing, via a sensor in a second anatomical location different than thefirst anatomical location, sensor data indicative of one or morenon-electrical heart activity properties in response to delivering thefirst series of electrical signals and the second series of electricalsignals, and providing a therapeutic neuromodulation signal to the firstanatomical location using selected electrical parameters. The selectedelectrical parameters comprise a selected magnitude of the firstparameter and a selected magnitude of the second parameter. The selectedmagnitudes of the first and second parameters are based at leastpartially on the sensor data. The therapeutic neuromodulation signalincreases heart contractility.

The method may further comprise delivering a third series of electricalsignals to the electrode. The third series comprises a third pluralityof electrical signals. Each of the third plurality of electrical signalscomprises the plurality of parameters. Each of the third plurality ofelectrical signals of the third series only differs from one another bya magnitude of a third parameter of the plurality of parameters. Thethird parameter is different than the first parameter and the secondparameter. The method may further comprise sensing, via the sensor,sensor data indicative of the one or more non-electrical heart activityproperties in response to delivering the third series of electricalsignals. The selected electrical parameters may comprise a selectedmagnitude of the third parameter. The selected magnitude of the thirdparameter is based at least partially on the sensor data.

The method may further comprise determining a desired hierarchy betweenthe first series and the second series. The first anatomical locationmay comprise a right pulmonary artery. The pulmonary artery may comprisea left pulmonary artery. The pulmonary artery may comprise a pulmonarytrunk. The one or more non-electrical heart activity properties maycomprise at least one of a pressure property, an acceleration property,an acoustic property, a temperature, and a blood chemistry property.Sensing the sensor data may comprise determining, via a second sensor ona skin surface, sensor data indicative of an electrocardiogram propertyin response to delivering the first series of electrical signals and thesecond series of electrical signals.

The first parameter may one of the following: a polarity, a pulsingmode, a pulse width, an amplitude, a frequency, a phase, a voltage, acurrent, a duration, an inter-pulse interval, a duty cycle, a dwelltime, a sequence, a wavelength, or a waveform, and, optionally, thesecond parameter may be a different one of the following: a polarity, apulsing mode, a pulse width, an amplitude, a frequency, a phase, avoltage, a current, a duration, an inter-pulse interval, a duty cycle, adwell time, a sequence, a wavelength, or a waveform. The secondparameter may one of the following: a polarity, a pulsing mode, a pulsewidth, an amplitude, a frequency, a phase, a voltage, a current, aduration, an inter-pulse interval, a duty cycle, a dwell time, asequence, a wavelength, or a waveform. The first parameter may comprisecurrent and the second parameter may comprise a parameter related totiming (e.g., one of frequency and duty cycle).

In some embodiments, a method of facilitating therapeuticneuromodulation of a heart of a patient comprises delivering a firstelectrical signal of a series of electrical signals to an electrode in afirst anatomical location, and, after delivering the first electricalsignal, delivering a second electrical signal of the series ofelectrical signals to the electrode. The second electrical signaldiffers from the first electrical signal by a magnitude of a firstparameter of a plurality of parameters. The method further comprisessensing, via a sensor in a second anatomical location different than thefirst anatomical location, sensor data indicative of one or morenon-electrical heart activity properties in response to the delivery ofthe series of electrical signals, and providing a therapeuticneuromodulation signal to the first anatomical location using selectedelectrical parameters. The selected electrical parameters comprise aselected magnitude of the first parameter. The selected magnitude of thefirst parameter is based at least partially on the sensor data. Thetherapeutic neuromodulation signal increases heart contractility.

The first anatomical location may comprise a right pulmonary artery. Thefirst anatomical location may comprise a left pulmonary artery. Thefirst anatomical location may comprise a pulmonary trunk. The one ormore non-electrical heart activity properties may comprise at least oneof a pressure property, an acceleration property, an acoustic property,a temperature, and a blood chemistry property. Sensing the sensor datamay comprise sensing, via a second sensor on a skin surface of thepatient, sensor data indicative of an electrocardiogram property inresponse to delivering the series of electrical signals. The firstparameter may be one of the following: a polarity, a pulsing mode, apulse width, an amplitude, a frequency, a phase, a voltage, a current, aduration, an inter-pulse interval, a duty cycle, a dwell time, asequence, a wavelength, or a waveform.

In some embodiments, a neuromodulation system for facilitating deliveryof electric signals to a heart of a patient comprises a catheter and astimulation system. The catheter comprises a catheter body comprising aproximal end, a distal end, a lumen extending from the proximal endtowards the distal end, and an outer surface. The catheter furthercomprises an electrode on the outer surface. The electrode is configuredto deliver an electrical signal to a pulmonary artery of a patient. Thecatheter further comprises a sensor on the outer surface. The sensor isconfigured to sense a heart activity property from a location within invasculature of the patient. The stimulation system comprises a pulsegenerator configured to deliver a first series of electrical signals anda second series of electrical signals to the electrode. The first seriescomprises a first plurality of electrical signals. Each of the firstplurality of electrical signals comprises a plurality of parameters.Each of the first plurality of electrical signals of the first seriesonly differs from one another by a magnitude of a first parameter of theplurality of parameters. The second series comprises a second pluralityof electrical signals. Each of the second plurality of electricalsignals comprises the plurality of parameters. Each of the secondplurality of electrical signals of the second series only differs fromone another by a magnitude of a second parameter of the plurality ofparameters. The second parameter is different than the first parameter.The stimulation system further comprises a non-transitorycomputer-readable medium configured to store sensor data indicative ofone or more non-electrical heart activity properties in response todelivering the first series of electrical signals and the second seriesof electrical signals to the electrode, and a processor configured todetermine a selected magnitude of the first parameter and a selectedmagnitude of the second parameter based at least partially on the sensordata. The non-transitory computer readable medium is configured to storeselected electrical parameters including the selected magnitude of thefirst parameter and the selected magnitude of the second parameter. Thepulse generator is configured to deliver a therapeutic neuromodulationsignal to the electrode using selected electrical parameters.

In some embodiments, a neuromodulation system for facilitatingdelivery/of electric signals to a heart of a patient comprises acatheter and a stimulation system. The catheter comprises a catheterbody comprising a proximal end, a distal end, a lumen extending from theproximal end towards the distal end, and an outer surface. The catheterfurther comprises an electrode on the outer surface. The electrode isconfigured to deliver an electrical signal to a pulmonary artery of apatient. The catheter further comprises a sensor on the outer surface.The sensor is configured to sense a heart activity property from alocation within in vasculature of the patient. The stimulation systemcomprises a pulse generator configured to deliver a series of electricalsignals to the electrode. The series comprises a first electrical signaland a second electrical signal. The second electrical signal differsfrom the first electrical signal by a magnitude of a first parameter ofa plurality of parameters. The stimulation system further comprises anon-transitory computer-readable medium configured to store sensor dataindicative of one or more non-electrical heart activity properties inresponse to delivering the series of electrical signals to theelectrode, and a processor configured to determine a selected magnitudeof the first parameter based at least partially on the sensor data. Thenon-transitory computer readable medium is configured to store selectedelectrical parameters including the selected magnitude of the firstparameter. The pulse generator is configured to deliver a therapeuticneuromodulation signal to the electrode using selected electricalparameters.

In some embodiments, a neuromodulation system for facilitating deliveryof electric signals to a heart of a patient comprises a catheter and ashaping wire. The catheter comprises a catheter body comprising aproximal end, a distal end, a lumen extending from the proximal endtowards the distal end, and an outer surface. The catheter furthercomprises an electrode on the outer surface. The electrode is configuredto deliver an electrical signal to a pulmonary artery of a patient. Theshaping wire is configured to be positioned in the lumen of the catheterbody. The shaping wire comprises a bent portion. When the shaping wireis inserted in the lumen of the catheter body, the catheter bodycomprises a curved portion corresponding to the bent portion of theshaping wire.

The heart activity property may comprise a non-electrical heartyactivity property. The non-electrical heart activity property maycomprise at least one of a pressure property, an acceleration property,an acoustic property, a temperature, and a blood chemistry property. Theelectrode may be configured to deliver the electrical signal to a rightpulmonary artery of the patient. The electrode may be configured to bepositioned in a different location than the sensor. The catheter systemmay comprise a plurality of electrodes including the electrode. Thelocation may be a pulmonary trunk, a right ventricle, a septal wall of aright ventricle, a right atrium, a septal wall of a right atrium, asuperior vena cava, a pulmonary branch artery vessel, an inferior venacava, or a coronary sinus. The neuromodulation system may furthercomprise a skin sensor configured to sense a cardiac property from askin surface of the patient. The heart activity property may comprise anon-electrical heart activity property and wherein the cardiac propertymay comprise an electrical cardiac property. The electrical cardiacproperty may comprise an electrocardiogram property.

In some embodiments, a method of neuromodulation of a heart of a patientcomprises positioning a catheter including an electrode in a pulmonaryartery of a heart, positioning a sensor in a location within vasculatureof the heart, delivering, via a stimulation system, a first set of oneor more electrical pulses to the electrode, the first set of one or moreelectrical pulses having a first pulse property, and, after deliveringthe first delivering set of one or more electrical pulses to theelectrode, delivering, via the stimulation system, a second set of oneor more electrical pulses to the electrode. The second set of one ormore electrical pulses has a second pulse property different than thefirst pulse property. The method further comprises deliveringtherapeutic electrical pulses to the pulmonary artery using an electrodeconfiguration selected by analyzing one or more heart activityproperties sensed, via the sensor, in response to the delivery of thefirst and second sets of electrical pulses. The electrode configurationcomprises the first pulse property or the second pulse property based atleast partially on the analysis. The therapeutic neuromodulation signalincreases heart contractility more than heart rate.

In some embodiments, a method of modulation (e.g., electricalneuromodulation) of a heart of a patient comprises delivering one ormore electrical pulses through a catheter positioned in a pulmonaryartery of the heart of the patient, sensing from at least a first sensorpositioned at a first location within a vasculature of the heart one ormore non-electrical heart activity properties in response to the one ormore electrical pulses, and adjusting a property of the one or moreelectrical pulses delivered through the catheter positioned in thepulmonary artery of the heart in response to the one or morenon-electrical heart activity properties.

In some embodiments, sensing from at least the first sensor positionedat the first location may include sensing one or more of a pressureproperty, an acceleration property, an acoustic property, a temperature,and a blood chemistry property from within the vasculature of the heart.

In one embodiment, a first sensor is placed in one of a left pulmonaryartery, a right pulmonary artery, or a pulmonary trunk of the heart. Oneor more electrical pulses are delivered through the catheter positionedin one of the left pulmonary artery, the right pulmonary artery, or thepulmonary trunk of the heart that does not contain the first sensor.

The first sensor may be positioned in the left pulmonary artery. Thefirst sensor may be positioned in the right pulmonary artery. The firstsensor may be positioned in other vessels in and around the heart,including, but not limited to, the pulmonary trunk, a pulmonary arterybranch vessel, right ventricle, a septal wall of the right ventricle, aright atrium, the septal wall of the right atrium, a superior vena cava,an inferior vena cava or a coronary sinus The first sensor (e.g., in thecoronary sinus) may sense at least one of a temperature or a bloodoxygen level.

In several embodiments, the method may include sensing one or morecardiac properties from a skin surface of the patient and adjusting theproperty of the one or more electrical pulses delivered through thecatheter positioned in the pulmonary artery of the heart in response tothe one or more non-electrical heart activity properties and the one ormore cardiac properties from the skin surface of the patient. The one ormore cardiac properties sensed from the skin surface of the patient mayinclude an electrocardiogram property. The may include sensing from atleast a second sensor positioned at a second location within thevasculature of the heart one or more non-electrical heart activityproperties in response to the one or more electrical pulses andadjusting the property of the one or more electrical pulses deliveredthrough the catheter positioned in the pulmonary artery of the heart inresponse to the one or more non-electrical heart activity propertiesreceived by the first sensor and the second sensor. In severalembodiments, adjusting the property of the one or more electrical pulsesmay include one or more of the following (i) changing which electrode onthe catheter is used to deliver the one or more electrical pulses; (ii)moving the catheter to reposition electrodes of the catheter in thepulmonary artery of the heart; (iii) changing at least one of anelectrode polarity, a pulsing mode, a pulse width, an amplitude, afrequency, a phase, a voltage, a current, a duration, an inter-pulseinterval, a duty cycle, a dwell time, a sequence, a wavelength, or awaveform of the one or more electrical pulses.

In several embodiments, the method may include assigning a hierarchy ofelectrode configurations from which to deliver the one or moreelectrical pulses, delivering the one or more electrical pulses based atleast partially on the hierarchy of electrode configurations, analyzingthe one or more non-electrical heart activity properties sensed inresponse to the one or more electrical pulses, and selecting anelectrode configuration to use for delivering the one or more electricalpulses through the catheter positioned in the pulmonary artery of aheart of a patient based at least partially on the analysis. The methodmay include assigning a hierarchy to each property of the one or moreelectrical pulses delivered through the catheter positioned in thepulmonary artery of the heart, delivering the one or more electricalpulses based at least partially on the hierarchy of each property,analyzing the one or more non-electrical heart activity propertiessensed in response to the one or more electrical pulses, and selectingan electrode configuration to use for delivering the one or moreelectrical pulses through the catheter positioned in the pulmonaryartery of a heart of a patient based at least partially on the analysis.Analyzing the one or more non-electrical heart activity properties mayinclude analyzing a predetermined number of the one or morenon-electrical heart activity properties.

In several embodiments, therapeutic neuromodulation is not provided.Instead, several embodiments are provided for the purposes ofcalibrating or optimizing a signal for, e.g., diagnosis or calibrationpurposes.

In some embodiments, a method of non-therapeutic calibration comprisespositioning an electrode in a pulmonary artery of a heart andpositioning a sensor in a right ventricle of the heart. The systemfurther comprises delivering, via a stimulation system, a first seriesof electrical signals to the electrode. The first series comprises afirst plurality of electrical signals. Each of the first plurality ofelectrical signals comprises a plurality of parameters. Each of thefirst plurality of electrical signals of the first series only differsfrom one another by a magnitude of a first parameter of the plurality ofparameters. The method further comprises, after delivering the firstseries of electrical signals to the electrode, delivering, via thestimulation system, a second series of electrical signals to theelectrode. The second series comprises a second plurality of electricalsignals. Each of the second plurality of electrical signals comprisesthe plurality of parameters. Each of the second plurality of electricalsignals of the second series only differs from one another by amagnitude of a second parameter of the plurality of parameters. Thesecond parameter is different than the first parameter. The methodfurther comprises determining, via the sensor, sensor data indicative ofone or more non-electrical heart activity properties in response todelivering the first series of electrical signals and the second seriesof electrical signals. The method further comprises determining atherapeutic neuromodulation signal to be delivered to the pulmonaryartery using selected electrical parameters. The selected electricalparameters comprise a selected magnitude of the first parameter and aselected magnitude of the second parameter. The selected magnitudes ofthe first and second parameters are based at least partially on thesensor data.

In some embodiments, a method of non-therapeutic calibration comprisesdelivering a first electrical signal of a series of electrical signalsto an electrode in a first anatomical location and, after delivering thefirst electrical signal, delivering a second electrical signal of theseries of electrical signals to the electrode. The second electricalsignal differs from the first electrical signal by a magnitude of afirst parameter of a plurality of parameters. The method furthercomprises sensing, via a sensor in a second anatomical locationdifferent than the first anatomical location, sensor data indicative ofone or more non-electrical heart activity properties in response to thedelivery of the series of electrical signals, and determining atherapeutic neuromodulation signal to be delivered to the firstanatomical location using selected electrical parameters. The selectedelectrical parameters comprise a selected magnitude of the firstparameter. The selected magnitude of the first parameter is based atleast partially on the sensor data.

The methods summarized above and set forth in further detail belowdescribe certain actions taken by a practitioner; however, it should beunderstood that they can also include the instruction of those actionsby another party. Thus, actions such as “positioning an electrode”include “instructing positioning of an electrode.”

For purposes of summarizing the invention and the advantages that may beachieved, certain objects and advantages are described herein. Notnecessarily all such objects or advantages need to be achieved inaccordance with any particular embodiment. In some embodiments, theinvention may be embodied or carried out in a manner that can achieve oroptimize one advantage or a group of advantages without necessarilyachieving other objects or advantages.

The embodiments disclosed herein are intended to be within the scope ofthe invention herein disclosed. These and other embodiments will beapparent from the following detailed description having reference to theattached figures, the invention not being limited to any particulardisclosed embodiment(s). Optional and/or preferred features describedwith reference to some embodiments may be combined with and incorporatedinto other embodiments. All references cited herein, including patentsand patent applications, are incorporated by reference in theirentirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A through 1C are schematic illustrations of a heart andsurrounding areas from various perspectives.

FIGS. 2A through 2C are side partial cross-sectional and perspectiveviews of an example catheter that is suitable for performing the methodsof the present disclosure.

FIG. 2D illustrates the catheter of FIGS. 2A through 2C positioned inthe right pulmonary artery of a heart.

FIG. 3 is partial cross-sectional and perspective view of an examplecatheter positioned in a heart of a patient.

FIG. 4 is a side partial cross-sectional and perspective view of anexample first catheter and an example second catheter that are suitablefor performing the methods of the present disclosure.

FIG. 5 is a block diagram of an example algorithm that can be used todetermine action taken by a controller microprocessor in response tosensor input.

DETAILED DESCRIPTION

Several embodiments of the present disclosure provide for methods anddevices that can be used to apply electrical neuromodulation to one ormore nerves in and around the heart of a patient. Several embodiments,for example, may be useful in electrical neuromodulation of patientswith cardiovascular medical conditions, such as patients with acute orchronic cardiac disease. As discussed herein, several embodiments canallow for a portion of a catheter to be positioned within thevasculature of the patient in at least one of the right pulmonaryartery, the left pulmonary artery, and the pulmonary trunk. Oncepositioned, an electrode system of the catheter can provide electricalpulses to stimulate the autonomic nervous system surrounding (e.g.,proximate to) the pulmonary artery in an effort to provide adjuvantcardiac therapy to the patient. Sensed heart activity properties (e.g.,non-electrical heart activity properties) can be used as the basis formaking adjustments to one or more properties of the one or moreelectrical pulses delivered through the catheter positioned in thepulmonary artery of the heart in an effort to provide adjuvant cardiactherapy to the patient.

Certain groups of figures showing similar items follow a numberingconvention in which the first digit or digits correspond to the drawingfigure number and the remaining digits identify an element or componentin the drawing. Similar elements or components between such groups offigures may be identified by the use of similar digits. For example, 110may reference element “10” in FIG. 1, and a similar element “10” may bereferenced as 210 in FIG. 2. As will be appreciated, elements shown inthe various embodiments herein can be added, exchanged, and/oreliminated so as to provide any number of additional embodiments of thepresent disclosure.

The terms “distal” and “proximal” are used herein with respect to aposition or direction relative to the treating clinician taken along thedevices of the present disclosure. “Distal” or “distally” are a positiondistant from or in a direction away from the clinician taken along thecatheter. “Proximal” and “proximally” are a position near or in adirection toward the clinician taken along the catheter.

In several embodiments, the catheters provided herein include aplurality of electrodes, which includes two or more electrodes. It isunderstood that the phrase “a plurality of electrodes” can be replacedherein with two or more electrodes if desired. With respect to treatingcardiovascular medical conditions, such medical conditions can involvemedical conditions related to the components of the cardiovascularsystem such as, for example, the heart and/or aorta. Non-limitingexamples of cardiovascular conditions include post-infarctionrehabilitation, shock (hypovolemic, septic, neurogenic), valvulardisease, heart failure, angina, microvascular ischemia, myocardialcontractility disorder, cardiomyopathy, hypertension including pulmonaryhypertension and systemic hypertension, orthopnea, dyspenea, orthostatichypotension, dysautonomia, syncope, vasovagal reflex, carotid sinushypersensitivity, pericardial effusion, heart failure, and cardiacstructural abnormalities such as septal defects and wall aneurysms.

In some embodiments, a catheter, for example as discussed herein, can beused in conjunction with a pulmonary artery catheter, such as aSwan-Ganz type pulmonary artery catheter, to deliver transvascularneuromodulation via the pulmonary artery to an autonomic target site totreat a cardiovascular condition. In certain such embodiments, thecatheter is housed within one of the multiple lumens of a pulmonaryartery catheter. Examples of catheters include those discussed hereinand those disclosed in U.S. Provisional Patent Application No.62/001,729, entitled “Catheter and Catheter System for ElectricalNeuromodulation” and filed on May 22, 2014; PCT Patent Application No.PCT/US2015/179634, entitled “Catheter and Catheter System for ElectricalNeuromodulation” and filed on May 21, 2015; U.S. Provisional PatentApplication No. 62/047,270, entitled “Catheter and Electrode Systems forElectrical Neuromodulation” and filed on Sep. 8, 2014; PCT PatentApplication No. PCT/US2015/047770, entitled “Catheter and ElectrodeSystems for Electrical Neuromodulation” and filed on Aug. 31, 2015; andU.S. patent application Ser. No. 14/085,311, entitled “Methods andSystems for Treating Acute Heart Failure by Neuromodulation” and filedon Nov. 20, 2013, where the contents of these applications areincorporated herein by reference in their entirety.

Several embodiments of the present disclosure provides methods that canbe used to treat acute heart failure, also known as decompensated heartfailure, by modulating the autonomic nervous system surrounding thepulmonary artery (e.g., the right pulmonary artery, the left pulmonaryartery, the pulmonary trunk) in an effort to provide adjuvant cardiactherapy to the patient. The neuromodulation treatment can help byaffecting heart contractility more than heart rate. In a preferredembodiment, the autonomic nervous system is modulated so as tocollectively affect heart contractility more than heart rate. Theautonomic nervous system can be impacted by electrical modulation thatincludes stimulating and/or inhibiting nerve fibers of the autonomicnervous system.

In some embodiments, systems other than intravascular catheters may beused in accordance with the methods described herein. For example,electrodes, sensors, and the like may be implanted during open heartsurgery or without being routed through vasculature.

Several embodiments, as will be discussed more fully herein, may allowfor the electrical neuromodulation of the heart of the patient thatincludes delivering one or more electrical pulses through a catheterpositioned in a pulmonary artery of the heart of the patient, sensingfrom at least a first sensor positioned at a first location within thevasculature of the heart one or more heart activity properties (e.g.,non-electrical heart activity properties) in response to the one or moreelectrical pulses, and adjusting a property of the one or moreelectrical pulses delivered through the catheter positioned in thepulmonary artery of the heart in response to the one or more heartactivity properties in an effort to provide adjuvant cardiac therapy tothe patient.

The catheter can include a plurality of electrodes, which are optionallyinserted into the pulmonary trunk, and positioned such that theelectrodes are, preferably, in contact with the posterior surface, thesuperior surface, and/or the inferior surface of the pulmonary artery.From such locations, electrical pulses can be delivered to or from theelectrodes to selectively modulate the autonomic nervous system of theheart. For example, electrical pulses can be delivered to or from one ormore of the electrodes to selectively modulate the autonomiccardiopulmonary nerves of the autonomic nervous system, which canmodulate heart contractility more than heart rate. Preferably, theplurality of electrodes is positioned at a site along the posterior walland/or superior wall of the pulmonary artery, for example the rightpulmonary artery. From such a position in the pulmonary artery, one ormore electrical pulses can be delivered through the electrodes and oneor more heart activity properties (e.g., non-electrical heart activityproperties) can be sensed. Based at least in part on these sensed heartactivity properties, a property of the one or more electrical pulsesdelivered to or from the electrodes positioned in the pulmonary arteryof the heart can be adjusted in an effort to positively influence heartcontractility while reducing or minimizing the effect on heart rateand/or oxygen consumption. In certain embodiments, the effect on heartcontractility is to increase heart contractility.

Referring now to FIGS. 1A through 1C, there is shown a schematicillustration of the human heart 100, where portions of the heart (e.g.,the aorta, the superior vena cava, among other structures), including aportion of the pulmonary trunk 102, have been removed to allow for thedetails discussed herein to be shown. FIG. 1A provides a perspectiveview of the heart 100 as seen from the front of the patient (viewed inan anterior to posterior direction), while FIG. 1B provides aperspective view of the heart 100 as seen from the right side of thepatient. As illustrated, the heart 100 includes the pulmonary trunk 102that begins at the base of the right ventricle 104. In an adult, thepulmonary trunk 102 is a tubular structure approximately 3 centimeters(cm) in diameter and 5 cm in length. The pulmonary trunk 102 branchesinto the left pulmonary artery 106 and the right pulmonary artery 108 ata branch point 110. The left pulmonary artery 106 and the rightpulmonary artery 108 serve to deliver de-oxygenated blood to eachcorresponding lung.

The branch point 110 includes a ridge 112 that extends from theposterior of the pulmonary trunk 102. As illustrated, the branch point110, along with the ridge 112, provides a “Y” or “T” shaped structurethat helps to define at least a portion of the left pulmonary artery 106and the right pulmonary artery 108. For example, from the ridge 112, thebranch point 110 of the pulmonary trunk 102 slopes in oppositedirections. In a first direction, the pulmonary trunk 102 transitionsinto the left pulmonary artery 106, and in the second direction,opposite the first direction, the pulmonary trunk 102 transitions intothe right pulmonary artery 108. The branch point 110 may not necessarilybe aligned along a longitudinal center line 114 of the pulmonary trunk102.

As illustrated in FIG. 1A, portions of the pulmonary artery 102 can bedefined with a right lateral plane 116 that passes along a right luminalsurface 118 of the pulmonary trunk 102, a left lateral plane 120parallel with the right lateral plane 116, where the left lateral plane120 passes along a left luminal surface 122 of the pulmonary artery 102.The right lateral plane 116 and the left lateral plane 120 extend inboth a posterior direction 124 and anterior direction 126. Asillustrated, the ridge 112 of the branch point 110 is located betweenthe right lateral plane 116 and the left lateral plane 120. The branchpoint 110 is positioned between the right lateral plane 116 and the leftlateral plane 120, where the branch point 110 can help to at leastpartially define the beginning of the left pulmonary artery 106 and theright pulmonary artery 108 of the heart 100. The distance between theright lateral plane 116 and the left lateral plane 120 is approximatelythe diameter of the pulmonary trunk 102 (e.g., about 3 cm).

As discussed herein, the present disclosure includes methods forelectrical neuromodulation of the heart 100 of the patient. For example,as discussed herein, a catheter positioned in the pulmonary artery 102of the patient can be used to deliver one or more electrical pulses tothe heart 100. A first sensor, for example as discussed herein,positioned at a first location within the vasculature of the heart 100senses one or more heart activity properties (e.g., non-electrical heartactivity properties) in response to the one or more electrical pulses.Properties of the one or more electrical pulses delivered through thecatheter positioned in the pulmonary artery 102 of the heart 100 canthen be adjusted in response to the one or more heart activityproperties in an effort to provide adjuvant cardiac therapy to thepatient.

FIG. 1C provides an additional illustration the posterior surface 121,the superior surface 123, and the inferior surface 125 of the rightpulmonary artery 108. As illustrated, the view of the heart 100 in FIG.1C is from the right side of the heart 100. As illustrated, theposterior surface 121, the superior surface 123, and the inferiorsurface 125 account for approximately three quarters of the luminalperimeter of the right pulmonary artery 108, where the anterior surface127 accounts for the remainder. FIG. 1C also illustrates the aorta 130,pulmonary veins 132, the superior vena cava (SVC) 134, and the inferiorvena cava (IVC) 136.

Referring now to FIGS. 2A through 2C, there are shown perspective viewsof an example catheter 230 that is suitable for performing certainmethods of the present disclosure. The catheter 230 includes an elongatecatheter body 232 having a proximal or first end 234 and a distal orsecond end 236. The elongate catheter body 232 also includes an outer orperipheral surface 238 and an interior surface 240 defining a lumen 242(shown with a broken line) that extends between the first end 234 andthe second end 236 of the elongate catheter body 232.

The catheter 230 further includes a plurality of electrodes 244positioned along the peripheral surface 238 of the elongate catheterbody 232. In some embodiments, the electrodes 244 are proximate to adistal end 236 of the catheter 230. Conductive elements 246 extendthrough the elongate body 232, where the conductive elements 246 can beused, as discussed herein, to conduct electrical pulses to combinationsof the plurality of electrodes 244. Each of the plurality of electrodes244 is coupled (e.g., electrically coupled) to a correspondingconductive element 246. The conductive elements 246 are electricallyisolated from each other and extend through the elongate body 232 fromeach respective electrode 244 through the first end 234 of the elongatebody 232. The conductive elements 246 terminate at a connector port,where each of the conductive elements 246 can be releasably coupled to astimulation system. It is also possible that the conductive elements 246are permanently coupled to the stimulation system (e.g., not releasablycoupled). As discussed more fully herein, the stimulation system can beused to provide stimulation electrical pulses that are conducted throughthe conductive elements 246 and delivered across combinations of theplurality of electrodes 244. Other positions and configurations ofelectrodes are also possible, for example the electrodes described inthe applications incorporated herein by reference (e.g., the electrodeson deployable filaments such as described in PCT Patent App. Nos.PCT/US2015/031960 and PCT/US2015/047770, the electrode matrix such asdescribed in PCT Patent App. Nos. PCT/US2015/047770 andPCT/US2015/047780, and others).

The elongate body 232 may comprise (e.g., be at least partially formedof) an electrically insulating material. Examples of such insulatingmaterial can include, but are not limited to, medical gradepolyurethanes, such as polyester-based polyurethanes, polyether-basedpolyurethanes, and polycarbonate-based polyurethanes; polyamides,polyamide block copolymers, polyolefins such as polyethylene (e.g., highdensity polyethylene); and polyimides, among others.

The catheter 230 optionally includes an anchor 248. The anchor 248includes struts 250 that form an open framework, where the struts 250extend laterally or radially outwardly from the elongate body 232 (e.g.,from a peripheral surface 238 of the elongate body 232) to at leastpartially define a peripheral surface 252 configured to engage vasculartissue (e.g., configured to appose sidewalls forming the lumen of theright pulmonary artery and/or the left pulmonary artery). FIGS. 2Athrough 2C show the anchor 248 positioned between the second end 236 andthe plurality of electrodes 244 of the elongate catheter body 232. It isalso possible that the anchor 248 can be positioned between theplurality of electrodes 244 and the second end 236 of the elongatecatheter body 232. In some embodiments, the anchor 248 can inhibit orprevent at least a portion of the catheter 230 (e.g., the portion 254, aportion comprising the electrodes 244) from extending into vasculaturesmaller than the expanded struts 250. For example, with reference toFIG. 3, the plurality of electrodes 344 can be proximal to the branchpoint 310 such that portions of the catheter 330 proximal to the anchor348 do not extend into the two additional arteries 378. If the sensor366 is distal to the anchor 348, interaction of the anchor 348 and thebranch point 310 may ensure that the sensor 366 is in a pulmonary arterybranch vessel 378.

The struts 250 can have a cross-sectional shape and dimension that allowfor the struts 250 to provide a radial force sufficient to hold thecatheter 230 at the implant location within the pulmonary artery under avariety of situations, as discussed herein. The struts 250 can be formedof a variety of materials, such as a metal, metal alloy, polymer, etc.Examples of such metals or metal alloys include surgical grade stainlesssteel, such as austenitic 316 stainless among others, and the nickel andtitanium alloy known as Nitinol. Other metals and/or metal alloys, asare known or may be developed, can be used.

A portion 254 of the elongate catheter body 232, for example thatincludes one, some, none, or all the plurality of electrodes 244, cancurve in a predefined radial direction (e.g., anterior, posterior,inferior, superior, and combinations thereof), for example when placedunder longitudinal compression. To provide the curve in the portion 254,the elongate catheter body 232 can be pre-stressed and/or the wall canhave thicknesses that allow for the elongate catheter body 232 to curvein the predefined radial direction, for example when placed underlongitudinal compression. In addition, or alternatively, structures suchas coils or a helix of wire having different turns per unit length, ahypotube having varying kerf spacing, etc. can be located in, around,and/or along the elongate catheter body 232 in the portion 254. One ormore of these structures can be used to allow the longitudinalcompression to create the curve in the predefined radial direction inthe portion 254. To achieve the longitudinal compression, the anchor 248can be deployed in the vasculature of the patient (e.g., in thepulmonary artery), where the anchor 248 provides a location or point ofresistance against the longitudinal movement of the elongate body 232.As such, this allows a compressive force to be generated in the elongatecatheter body 232 sufficient to cause the portion 254 of the elongatecatheter body 232, for example along which the plurality of electrodes244 are present, to curve in the predefined radial direction.

FIG. 2D provides an illustration of the portion 254 of the elongatecatheter body 232 curved in a predefined radial direction when placedunder longitudinal compression. The catheter 230 illustrated in FIG. 2Dis similar to the catheter 230 shown in FIG. 2A and is described herein,although other catheters having similar features can also be used. Inthe catheter 230 illustrated in FIG. 2D, the sensor 266 is proximal tothe electrodes 244. When the electrodes are in the right pulmonaryartery 208, the sensor 266 can be in the pulmonary trunk 202, forexample. If the sensor 266 is more proximal, the sensor 266 can be inthe right ventricle, the superior vena cava, etc. Positioning the sensor266 proximal along the catheter 230 can allow the sensor 266 to be in alocation different than the location of the electrode 244 withoutpositioning the sensor 266 separate from positioning the electrode 244.As illustrated in FIG. 2D, the catheter 230 has been at least partiallypositioned within the main pulmonary artery 202 of a patient's heart200, where the anchor 248 is located in the lumen of the right pulmonaryartery 208. From this position, a longitudinal compressive force appliedto the elongate catheter body 232 can cause the portion 254 of theelongate catheter body 232, along with at least some of the plurality ofelectrodes 244 in this embodiment, to curve in the predefined radialdirection, superior in this embodiment. The curvature allows theplurality of electrodes 244 to extend towards and/or touch the luminalsurface of the main and/or right pulmonary artery. Preferably, theplurality of electrodes 244 are brought into position and/or contactwith the luminal surface of the main and/or right pulmonary artery.

In some embodiments, the elongate catheter body 232 of the catheter 230can use the lumen 242 that extends from the first end 234 towards thesecond end 236 to provide a curve in a predefined radial direction. Forexample, the catheter 230 can include a shaping wire 257 having a firstend 259 and a second end 261, as illustrated in FIG. 2A. The shapingwire 257 can be bent and retain a desired shape that, upon insertioninto the lumen 242, can at least partially provide the catheter 230 witha curve. The lumen 242 has a size (e.g., a diameter) sufficient to allowthe shaping wire 257 to pass through the lumen 242 with the second end261 of the shaping wire 257 proximate to the second end 236 of theelongate catheter body 232 so that the bent portion 263 of the shapingwire 257 imparts a curve into the portion 254 of the elongate catheterbody 232, allowing the plurality of electrodes 244 to extend towardsand/or touch the luminal surface of the main pulmonary artery. In someembodiments the shaping wire 257 can complement the portion 254. In someembodiments, the shaping wire 257 can be used in place of the portion254 (e.g., if the catheter 230 does not include the portion 254 or bynot imparting the longitudinal compressive force). In some embodiments,the shaping wire 257 can be used to impart a curve that is contrary tothe curve that the portion 254 would cause if a compressive force wasapplied. In some embodiments, the shaping wire 257 may be inserted intothe lumen 242 in any rotational orientation such that a curve can beimparted in any desired radial direction, for example depending on theposition of the anchor 248. The shaping wire 257 can allow formation ofa curve even if the catheter 230 does not include an anchor 248, forexample because the catheter body 232 can conform to the shape of theshaping wire regardless of whether the catheter 230 is anchored to thevasculature. In some embodiments, insertion of the shaping wire 257 intothe lumen 242 imparts a curve to the portion 254 such that at least oneof the electrodes 244 apposes a superior/posterior sidewall of thepulmonary artery.

In some embodiments, a neuromodulation system comprises a catheter 230and a shaping wire 257. The catheter 230 comprises a catheter body 232,an electrode 244, and a sensor 266. The catheter body 232 comprises aproximal end 234, a distal end 236, a lumen 242 extending from theproximal end 234 towards the distal end 236 (e.g., at least distal tothe electrode 244), and an outer surface 238. The electrode 244 is onthe outer surface 238. The electrode 244 is configured to deliver anelectrical signal to a pulmonary artery of a patient (e.g., to providecalibration and/or therapeutic stimulation to a nerve proximate thepulmonary artery).

The shaping wire 257 comprises a material that is configured to causethe catheter body 232 to bend. For example, the radial force of theshaping wire 257 may be greater than the forces that keep the catheterbody 232 in a generally straight configuration. In some embodiments, theshaping wire 257 comprises a shape memory material (e.g., nitinol,chromium cobalt, copper aluminum nickel, etc.) or a resilient material(e.g., stainless steel, etc.). For example, the shaping wire 257 may bestressed to a straight wire in a proximal portion of the catheter 230,but in a portion of the catheter 230 to be bent, which may be, forexample, weaker that the proximal portion of the catheter 230, theshaping wire 257 can revert to the unstressed curved shape within thecatheter 230. In some embodiments in which the shaping wire 257comprises a shape memory material, the shaping wire 257 may utilizethermal shape memory. For example, the shaping wire 257 may be in asubstantially straight shape until cold or warm fluid (e.g., saline)causes reversion to the curved shape. In some such embodiments, theentire catheter 230 may be bendable by the shaping wire 257, but thetemperature change is effected once the shaping wire 257 is in a desiredlongitudinal and/or radial position. In some embodiments, the entirecatheter 230 may be bendable by the shaping wire 257. For example, thecurve may propagate along the length of the catheter 230 until the curveis in a desired position.

The shaping wire 257 has a diameter or cross-sectional dimension lessthan the diameter or cross-sectional dimension of the lumen 242. Forexample, if the catheter body 232 is 20 French (Fr) (approx. 6.67millimeters (mm)), the lumen 242 may be 18 Fr (approx. 6 mm) and theshaping wire 257 may be 16 Fr (approx. 5.33 mm). The shaping wire 257may be, for example 1 Fr less than the lumen 242 (e.g., for more radialforce than if 2 Fr less) or 2 Fr less than the lumen 242 (e.g., for lessfriction during navigation than if 1 Fr less). The shaping wire 257 maybe, for example 2 Fr less than the catheter body 232 (e.g., if the lumen242 is 1 Fr less than the catheter body 232) or 4 Fr less than thecatheter body 232 (e.g., providing flexibility for the size of the lumen242 to be 1 or 2 Fr less than the catheter body). Shaping wire sizesother than on a French catheter scale are also possible (e.g., having adiameter less than a diameter of the lumen 242 by about 0.05 mm, 0.1 mm,by about 0.2 mm, by about 0.25 mm, by about 0.5 mm, ranges between suchvalues etc.).

The sensor 266 is on the outer surface 238. The sensor 266 is configuredto sense a heart activity property (e.g., a non-electrical heartactivity property such as a pressure property, an acceleration property,an acoustic property, a temperature, and a blood chemistry property)from a location within in vasculature of the patient. The location maybe different than the pulmonary artery in which the electrode 244 ispositioned. For example, if the electrode 244 is in the right pulmonaryartery, the location of the sensor 266 may be in the pulmonary trunk, apulmonary artery branch vessel, the right ventricle, the ventricularseptal wall, the right atrium, the septal wall of the right atrium, thesuperior vena cava, the inferior vena cava, the left pulmonary artery,the coronary sinus, etc. The shaping wire 257 is configured to bepositioned in the lumen 242 of the catheter body 232. The shaping wirecomprising a bent portion 263. For example, from a proximal end 259 to adistal end 261, the shaping wire 257 may be substantially straight in asubstantially straight portion, then have a bent portion 263 extendingaway from a longitudinal axis of the straight portion. The bent portion263 may include one bend or a plurality of bends (e.g., two bends (asillustrated in FIG. 2A), three bends, or more bends). The shaping wire257 may optionally comprise another substantially straight portion afterthe bent portion, which may have a longitudinal axis that issubstantially aligned with the longitudinal axis of the proximalstraight portion. When the shaping wire 257 is inserted in the lumen 242of the catheter body 232, the catheter body 232 comprises a curvedportion 254 corresponding to the bent portion 263 of the shaping wire257. For example, the catheter body 232, or the portion 254, maycomprise a material that can be bent due to pressure or stress appliedto the lumen 242 or interior surface 240 of the catheter body 232. Insome embodiments, insertion of the shaping wire 257 into the lumen 242imparts a curve to the portion 254 such that at least one of theelectrodes 244 apposes a superior/posterior sidewall of the pulmonaryartery.

FIGS. 2A through 2C further illustrate an example delivery catheter 256that can be used in conjunction with the catheter 230. The deliverycatheter 256 can be a Swan-Ganz type pulmonary artery catheter, as areknown, that includes a surface 258 defining a lumen 260 sizedsufficiently to receive, store, and deploy the catheter 230. Asillustrated, the delivery catheter 256 includes a reversibly inflatableballoon 262 in fluid communication with a balloon inflation lumen thatextends from a proximal or first end 264 of the delivery catheter 256(e.g., where the inflation lumen can be to an inflation fluid source) tothe interior volume of the reversibly inflatable balloon 262.

The catheter 230 also includes a first sensor 266. As illustrated inFIGS. 2A through 2C, the first sensor 266 can be positioned at a numberof different locations along the catheter 230. In FIG. 2A, the firstsensor 266 is positioned on the elongate catheter body 232 distal to theanchor 248. A sensor 266 that is proximate to the distal end 236 of thecatheter 230 may also or alternatively be useful for navigation of thecatheter 230, for example to determine an anatomical location duringfloating a balloon such as with a Swan-Ganz catheter. In FIG. 2B, thefirst sensor 266 is positioned on or between one of the struts 250 ofthe anchor. In FIG. 2C, the first sensor 266 is positioned proximal toboth the anchor 248 and the plurality of electrodes 244. In FIG. 2D, thefirst sensor 266 is positioned proximal enough that the first sensor 266can be in a location of the vasculature different than the electrodes244. In some embodiments, the catheter 230 comprises a plurality ofsensors 266 at more than one of the positions illustrated in FIGS. 2Athrough 2C and/or other positions.

The catheter 230 further includes a sensor conductor 268. The firstsensor 266 is coupled to the sensor conductor 268 and is isolated fromthe conductive elements 246 and electrodes 244. The coupling may beelectrical, optical, pressure, etc. The sensor conductor 268 extendsthrough the elongate body 232 from the first sensor 266 through thefirst end 234 of the elongate body 232. The sensor conductor 268terminates at a connector port that can be used, for example, toreleasably couple the first sensor 266 to the stimulation system, asdiscussed herein.

The first sensor 266 can be used to sense one or more activity property(e.g., electrical and/or non-electrical heart activity properties). Insome embodiments, the property can be measured in response to one ormore electrical pulses delivered using the plurality of electrodes 244.Examples of non-electrical heart activity properties include, but arenot limited to, one or more of a pressure property, an accelerationproperty, an acoustic property, a temperature, and a blood chemistryproperty measured from within the vasculature of the heart. Asappreciated, two or more of the non-electrical heart activity propertiescan be measured by using more than one sensor on the catheter 230.

For use in detecting a pressure property, the first sensor 266 can be apressure sensing transducer, for example such as disclosed in U.S. Pat.No. 5,564,434 (e.g., configured to detect changes in blood pressure,atmospheric pressure, and/or blood temperature and to provide modulatedpressure and/or temperature related signals), incorporated by referenceherein in its entirety. For use in detecting an acceleration property,the first sensor 266 can be an acceleration sensor, for example such asdisclosed in U.S. Patent Pub. No. 2004/0172079 to Chinchoy (e.g.,configured to generate a signal proportional to acceleration of a heartmuscle or wall such as a coronary sinus wall, septal wall, or ventriclewall) or U.S. Pat. No. 7,092,759 to Nehls et al. (e.g., configured togenerate a signal proportional to acceleration, velocity, and/ordisplacement of a heart muscle or wall such as a coronary sinus wall,septal wall, or ventricle wall), each of which is incorporated byreference herein in its entirety. For use in detecting an acousticproperty, the first sensor 266 can be a piezoelectric transducer (e.g.,a microphone) or a blood flow sensor, for example such as disclosed inU.S. Pat. No. 6,754,532 (e.g., configured to measure a velocity of bloodto estimate blood flow volume), which is incorporated by referenceherein in its entirety. For use in detecting a temperature, the firstsensor 266 can be a temperature sensor, for example such as disclosed inU.S. Pat. No. 5,336,244 (e.g., configured to detect variations in bloodtemperature and/or oxygen concentration indicative of the mechanicalpumping action of the heart) and/or U.S. Patent Pub. No. 2011/0160790(e.g., configured to sense temperature and to produce a temperaturesignal), each of which is incorporated by reference herein in itsentirety. For use in detecting a blood chemistry properties, the firstsensor 266 can be an oxygen sensor or a glucose sensor, for example suchas disclosed in U.S. Pat. No. 5,213,098 (e.g., configured to sense bloodoxygen saturation levels that vary with cardiac muscle oxygen uptake)and/or U.S. Patent Pub. No. 2011/0160790 (e.g., configured to measureoxygen and/or glucose concentration in blood and to produce an oxygenand/or glucose signal), each of which is incorporated by referenceherein in its entirety. Other types of sensors can also be used for thefirst sensor 266 and other sensors described herein.

The catheter 230 shown in FIGS. 2A through 2C can be positioned in theright pulmonary artery, the left pulmonary artery, or the pulmonarytrunk of the patient, as described herein. To accomplish this, thedelivery catheter 256 with the catheter 230 housed therein can beintroduced into the vasculature through a percutaneous incision, andguided to the right ventricle using known techniques. For example, thedelivery catheter 256 can be inserted into the vasculature via aperipheral vein of the neck or chest (e.g., as with a Swan-Ganzcatheter). Changes in a patient's electrocardiography and/or pressuresignals from the vasculature can be used to guide and locate thepulmonary artery catheter within the patient's heart. Once in the properlocation, a guide wire can be introduced into the patient via thepulmonary artery guide catheter, where the guide wire is advanced intothe desired pulmonary artery (e.g., the right pulmonary artery). Thedelivery catheter 256 with the catheter 230 housed therein can beadvanced over the guide wire so as to position the catheter 230 in thedesired pulmonary artery of the patient (e.g., the right pulmonaryartery or the left pulmonary artery), as described herein. Variousimaging modalities can be used in positioning the guide wire of thepresent disclosure in the pulmonary artery of the patient. Such imagingmodalities include, but are not limited to, fluoroscopy, ultrasound,electromagnetic, and electropotential modalities.

When the catheter 230 is positioned in the right pulmonary artery or theleft pulmonary artery and the sensor 266 is configured to be proximal tothe electrodes 244, a distance between the electrodes 244 (e.g., fromthe proximal-most electrode 244) and the sensor 266 may be between about1 cm and about 5 cm (e.g., about 1 cm, about 2 cm, about 3 cm, about 4cm, about 5 cm, ranges between such values, etc.), in which case thesensor 266 can reside in the pulmonary trunk, between about 8 cm andabout 20 cm (e.g., about 8 cm, about 9 cm, about 10 cm, about 11 cm,about 12 cm, about 13 cm, about 14 cm, about 16 cm, about 18 cm, about20 cm, ranges between such values, etc.), in which case the sensor 266can reside in the right ventricle, between about 16 cm and about 27 cm(e.g., about 16 cm, about 17 cm, about 18 cm, about 19 cm, about 20 cm,about 21 cm, about 22 cm, about 23 cm, about 25 cm, about 27 cm, rangesbetween such values, etc.), in which case the sensor 266 can reside inthe right atrium, or between about 21 cm and about 33 cm (e.g., about 21cm, about 23 cm, about 25 cm, about 26 cm, about 27 cm, about 28 cm,about 29 cm, about 30 cm, about 31 cm, about 32 cm, about 33 cm, rangesbetween such values, etc.), in which case the sensor 266 can reside inthe superior vena cava.

When the catheter 230 is positioned in the pulmonary trunk and thesensor 266 is configured to be distal to the electrodes 244, a distancebetween the electrodes 244 (e.g., from the distal-most electrode 244)and the sensor 266 may be between about 1 cm and about 5 cm (e.g., about1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, ranges betweensuch values, etc.), in which case the sensor 266 can reside in the rightpulmonary artery or the left pulmonary artery. When the catheter 230 ispositioned in the pulmonary trunk and the sensor 266 is configured to beproximal to the electrodes 244, a distance between the electrodes 244(e.g., from the proximal-most electrode 244) and the sensor 266 may bebetween about 3 cm and about 19 cm (e.g., about 3 cm, about 5 cm, about6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 12 cm,about 15 cm, about 19 cm, ranges between such values, etc.), in whichcase the sensor 266 can reside in the right ventricle, between about 11cm and about 26 cm (e.g., about 11 cm, about 13 cm, about 15 cm, about16 cm, about 17 cm, about 18 cm, about 19 cm, about 20 cm, about 22 cm,about 24 cm, about 26 cm, ranges between such values, etc.), in whichcase the sensor 266 can reside in the right atrium, or between about 16cm and about 32 cm (e.g., about 16 cm, about 18 cm, about 20 cm, about22 cm, about 24 cm, about 25 cm, about 26 cm, about 27 cm, about 28 cm,about 30 cm, about 32 cm, ranges between such values, etc.), in whichcase the sensor 266 can reside in the superior vena cava.

FIG. 3 provides a perspective view of the catheter 330 positioned in theheart 300 of the patient, where one or more of the plurality ofelectrodes 344 are contacting the posterior 321 and/or superior surface323 of the right pulmonary artery 308 (e.g., at a position that issuperior to the branch point 310). FIG. 3 further illustrates theembodiment in which the first sensor 366 is positioned distal from theanchor 348. As illustrated, the pulmonary trunk 302 has a diameter 370taken across a plane 372 substantially perpendicular to both the leftlateral plane 320 and the right lateral plane 316. In a preferredembodiment, the plurality of electrodes 344 of the catheter 330 ispositioned in an area 374 that extends distally no more than about threetimes the diameter 370 of the pulmonary trunk 302 to the right of thebranch point 310. This area 374 is shown with cross-hatching in FIG. 3.

The right pulmonary artery 308 can also include a branch point 376 thatdivides the right pulmonary artery 308 into at least two additionalarteries 378 that are distal to the branch point 310 defining the leftpulmonary artery 306 and the right pulmonary artery 308. As illustratedin FIG. 3, the plurality of electrodes 344 can be positioned between thebranch point 310 defining the left pulmonary artery 306 and the rightpulmonary artery 308 and the branch point 376 that divides the rightpulmonary artery 308 into at least two additional arteries 378. In otherwords, the plurality of electrodes 344 of the catheter 330 could bepositioned so as to contact the posterior 321 and/or superior surface323 of the right pulmonary artery 308 up to an including the branchpoint 376.

Once positioned in a pulmonary artery of the heart of the patient (e.g.,the right pulmonary artery 308 as illustrated in FIG. 3, the leftpulmonary artery 306, and/or the pulmonary trunk 302), one or moretherapeutic and/or calibrating electrical pulses can be deliveredthrough the plurality of electrodes 344 of the catheter 330. One or moreheart activity properties in response to the one or more electricalpulses are sensed from at least the first sensor 366 positioned at afirst location within the vasculature of the heart 300.

The catheter 230, 330 may be permanently or reversibly implantable intothe vasculature. For example, the catheter 230, 330 may be retractedfrom the vasculature (e.g., after removing the anchor 248, 348) after aduration. The duration may be determined based at least partially on aset duration (e.g., a certain number of hours or days (e.g., 12 hours,18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, etc.)). Theduration may be determined based at least partially on a response of apatient (e.g., retracted when the patient has improved in an aspect by acertain amount or is deemed ready to have the catheter 230, 330removed).

FIG. 4 illustrates an example catheter 430 and a separate first sensor466 useful for the methods of the present disclosure. Similar to thecatheter 230, the catheter 430 includes an elongate catheter body 432having a proximal or first end 434 and a distal or second end 436, aperipheral surface 438 and an interior surface 440 defining a lumen 442(shown with a broken line) that extends between the first end 434 andthe second end 436 of the elongate catheter body 432. The catheter 430further includes a plurality of electrodes 444 positioned along theperipheral surface 438 of the elongate catheter body 432, and conductiveelements 446 extending through the elongate body 432 between theplurality of electrodes 444 and the first end 434, as discussed herein.The catheter 430 further includes an anchor 448 comprising struts 450that provide a peripheral surface 452 that can engage vascular tissue(e.g., the lumen of either the right pulmonary artery or the leftpulmonary artery).

The catheter 430 further includes a portion 454 of the elongate catheterbody 432, for example including the plurality of electrodes 444, wherethe portion 454 can curve in a predefined radial direction when placedunder longitudinal compression, as discussed herein. The elongatecatheter body 432 of the catheter 430 can also or alternatively includea lumen 442 that can receive a shaping wire, as discussed herein.

In contrast to the catheter illustrated in FIGS. 2A through 2D, however,the catheter 430 does not include a first sensor. Rather, a secondcatheter 480 includes a first sensor 466. As illustrated in FIG. 4, thesecond catheter 480 includes an elongate catheter body 482 having afirst end 484 and a second end 486, a peripheral surface 488 and aninterior surface 490 defining a lumen 492 (shown with a broken line)that extends between the first end 484 and the second end 486 of theelongate catheter body 482, where the lumen 492 can receive a guide wirefor help in positioning the second catheter 480 in the vasculature ofthe heart. The second catheter 480 further includes a first sensor 466,as discussed herein, on the elongate catheter body 482 and a sensorconductor 468 that extends through the elongate catheter body 482 toterminate at a connector port that can be used, for example, toreleasably couple the first sensor 466 to the stimulation system, asdiscussed herein.

As the first sensor 466 is included on the second catheter 480, thefirst sensor 466 can be positioned in a location within the vasculatureof the patient that is different than the first location in which thecatheter 430 is positioned. For example, the catheter 430 can bepositioned with the plurality of electrodes 444 positioned in the rightpulmonary artery, as discussed herein, while the first sensor 466 ispositioned in the left pulmonary artery. In this way, one or moreelectrical pulses can be delivered through the catheter 430 positionedin the right pulmonary artery of the heart that does not contain thefirst sensor 466. In some embodiments, when the catheter 430 ispositioned with the plurality of electrodes 444 positioned in the leftpulmonary artery, the first sensor 466 can be positioned in the rightpulmonary artery. In this way, one or more electrical pulses can bedelivered through the catheter 430 positioned in the left pulmonaryartery of the heart that does not contain the first sensor 466.

In some embodiments, the catheter 430 can be positioned with theplurality of electrodes 444 positioned in either one of the leftpulmonary artery or the right pulmonary artery, and the first sensor 466on the second catheter 480 can be positioned in the right ventricle ofthe heart. The first sensor 466 on the second catheter 480 can also bepositioned in the right atrium of the heart.

In some embodiments, the first sensor 466 on the second catheter 480 canalso be positioned on the septal wall of the right atrium or theventricular septal wall of the heart. The elongate catheter body 482 ofthe second catheter 480 can include a positive fixation structure (e.g.,a helical screw) that helps to secure the elongate catheter body 482 andthe first sensor 466 to the septal wall of the right atrium of theheart.

In some embodiments the first sensor 466 on the second catheter 480 canbe positioned in a superior vena cava of the heart. In some embodiments,the first sensor 466 on the second catheter 480 can be positioned in aninferior vena cava of the heart. In some embodiments, the first sensor466 on the second catheter 480 can be positioned in a coronary sinus ofthe heart. In a preferred embodiment, when the first sensor 466 ispositioned in the coronary sinus of the heart, the first sensor 466 isused to sense at least one of a temperature and a blood oxygen level.

One or more cardiac properties can also or alternatively be sensed froma skin surface of the patient. An example of such a cardiac propertyincludes an electrocardiogram property, where the electrical activity ofthe heart can be sensed using electrodes, as are known, attached to thesurface of the patient's skin. Another example of such a cardiacproperty can include a doppler echocardiogram, which can be used todetermine the speed and direction of the blood flow. Acoustic signalssensed from the skin surface of the patient may also be used as thecardiac property. The properties of the one or more electrical pulsesdelivered through the catheter positioned in the pulmonary artery of theheart can then be adjusted, as discussed herein, in response to the oneor more heart activity properties measured intravascularly and/or theone or more cardiac properties from the skin surface of the patient.

In some embodiments, a second sensor located at a second location withinthe vasculature of the heart can be used, in addition to the firstsensor, to sense one or more heart activity properties, as discussedherein, for example in response to the one or more electrical pulses.The second location is different than the first location. For example,the first location may be the left pulmonary artery and the secondlocation may be the right pulmonary artery; the first location may bethe left pulmonary artery and the second location may be the pulmonarytrunk; the first location may be the left pulmonary artery and thesecond location may be the right ventricle; the first location may bethe left pulmonary artery and the second location may be the rightatrium; the first location may be the left pulmonary artery and thesecond location may be the septal wall of the right atrium; the firstlocation may be the left pulmonary artery and the second location may bethe ventricular septal wall; the first location may be the leftpulmonary artery and the second location may be the superior vena cava;the first location may be the left pulmonary artery and the secondlocation may be the inferior vena cava; the first location may be theleft pulmonary artery and the second location may be the coronary sinus;and other permutations of these locations.

In some embodiments, the second sensor is the sensor 466 of the secondcatheter 480, and the first sensor is the sensor 266 of the catheter230. In some embodiments the first sensor and the second sensor can belocated on the same catheter (e.g., the catheter 230, the catheter 480).For example, both the first sensor and the second sensor can be locatedon the second catheter 480 for sensing at least two different heartactivity properties. For another example, both the first sensor and thesecond sensor can be located on the catheter 230 for sensing at leasttwo different heart activity properties. The properties of the one ormore electrical pulses delivered through the catheter positioned in thepulmonary artery of the heart can be adjusted, as discussed herein, inresponse to the one or more heart activity properties received from thefirst sensor and the second sensor.

Neuromodulation of the heart according to the present disclosure can beaccomplished by applying electrical pulses in and/or around the regionof the pulmonary artery. For example, the neuromodulation of the presentdisclosure can apply the electrical pulses to the posterior, superiorwall, and/or the inferior wall of the right pulmonary artery.Preferably, neuromodulation of the present disclosure includes applyingthe electrical pulses to the posterior and/or superior wall of the rightpulmonary artery, although other positions in the right pulmonaryartery, the left pulmonary artery, and the pulmonary trunk are alsopossible. The electrical pulses are thereby applied to the autonomiccardiopulmonary nerves surrounding the right pulmonary artery. Theseautonomic cardiopulmonary nerves can include the right autonomiccardiopulmonary nerves and the left autonomic cardiopulmonary nerves.The right autonomic cardiopulmonary nerves include the right dorsalmedial cardiopulmonary nerve and the right dorsal lateralcardiopulmonary nerve. The left autonomic cardiopulmonary nerves includethe left ventral cardiopulmonary nerve, the left dorsal medialcardiopulmonary nerve, the left dorsal lateral cardiopulmonary nerve,and the left stellate cardiopulmonary nerve. Stimulation of other nervesproximate to the right pulmonary artery is also possible.

With reference FIG. 3, one or more of the plurality of electrodes 344 ofthe catheter 330 can be contacting the posterior surface 321 of theright pulmonary artery 308. From this location, the electrical pulsesdelivered through one or more of the plurality of electrodes 344 may bebetter able to treat and/or provide therapy (including adjuvant therapy)to the patient experiencing a variety of cardiovascular medicalconditions, such as acute heart failure. The electrical pulses canelicit responses from the autonomic nervous system that may help tomodulate a patient's cardiac contractility. The electrical pulsesapplied by the methods described herein preferably affect heartcontractility more than the heart rate, which can help to improvehemodynamic control while possibly and/or reducing or minimizingunwanted systemic effects.

A stimulation system is electrically coupled to the plurality ofelectrodes of the catheter via the conductive elements extending throughthe catheter. The stimulation system can be used to deliver theelectrical pulses to the autonomic cardiopulmonary fibers surroundingthe pulmonary artery (e.g., the right pulmonary artery). The stimulationsystem is used to operate and supply the electrical pulses to theplurality of electrodes of the catheter. The stimulation system controlsthe various properties of the electrical pulses delivered across theplurality of electrodes. Such properties include control of polarity(e.g., used as a cathode or an anode), pulsing mode (e.g., unipolar,bi-polar, biphasic, and/or multi-polar), a pulse width, an amplitude, afrequency, a phase, a voltage, a current, a duration, an inter-pulseinterval, a dwell time, a sequence, a wavelength, and/or a waveformassociated with the electrical pulses. The stimulation system mayoperate and supply the electrical pulses to different combinations andnumbers of the plurality of electrodes, including a reference electrode.The stimulation system can be external to the patient's body or internalto the patient's body. When located outside the body, a professional canprogram the stimulation system and monitor its performance. When locatedwithin the patient, the housing of the stimulation system or anelectrode incorporated in the housing can be used as a referenceelectrode for both sensing and unipolar pulsing mode.

Examples of non-electrical heart activity properties include, but arenot limited to, a pressure property, an acceleration property, anacoustic property, a temperature, or a blood chemistry property. Thenon-electrical heart activity properties may be sensed by at least afirst sensor positioned at a first location within the vasculature ofthe heart. In response to the one or more non-electrical heart activityproperties, a property of the one or more electrical pulses deliveredthrough the catheter positioned in the pulmonary artery of the heart canbe adjusted. Examples of such adjustments include, but are not limitedto, changing which electrode or electrodes of the plurality ofelectrodes on the catheter is/are used to deliver one or more electricalpulses. Adjustments can also be made to the properties of the electricalpulses, for example by changing at least one of an electrode polarity, apulsing mode, a pulse width, an amplitude, a frequency, a phase, avoltage, a current, a duration, an inter-pulse interval, a duty cycle, adwell time, a sequence, a wavelength, and a waveform of the one or moreelectrical pulses. It is possible to adjust combinations of electrodesused and the properties of the electrical pulses provided by theelectrodes. Adjusting a property of the one or more electrical pulsescan include moving the catheter to reposition electrodes of the catheterin the pulmonary artery of the heart. Combinations of these adjustmentsare also possible.

By way of example, the electrical pulses can have a voltage betweenabout 0.1 microvolts (mV) and about 75 volts (V) (e.g., about 0.1 mV,about 0.5 mV, about 1 mV, about 10 mV, about 100 mV or about 0.1 V,about 1 V, about 10 V, about 20 V, about 30 V, about 40 V, about 50 V,about 60 V, about 75 V, ranges between such values, etc.). Theelectrical pulses can also have an amplitude between about 1 milliamps(mA) to about 40 mA (e.g., about 1 mA, about 2 mA, about 3 mA, about 4mA, about 5 mA, about 10 mA, about 15 mA, about 20 mA, about 25 mA,about 30 mA, about 35 mA, about 40 mA, ranges between such values,etc.). The electrical pulses can be delivered at a frequency of between1 Hertz (Hz) and about 10,000 Hz or 10 kilohertz (kHz) (e.g., about 1Hz, about 2 Hz, about 10 Hz, about 25 Hz, about 50 Hz, about 75 Hz,about 100 Hz, about 150 Hz, about 200 Hz, about 250 Hz, about 500 Hz,about 1,000 Hz or 1 kHz, about 10 kHz, ranges between such values,etc.). The electrical pulses can have a pulse width between about 100microseconds (μs) and about 100 milliseconds (ms) (e.g., about 100 μs,about 200 μs, about 500 μs, about 1,000 μs or 1 ms, about 10 ms, about50 ms, about 100 ms, ranges between such values, etc.). For variation ofduty cycle, or the duration that the electrical pulses are deliveredversus the duration that electrical pulses are not delivered, theelectrical pulses may be delivered for between about 250 ms and about 1second (e.g., about 250 ms, about 300 ms, about 350 ms, about 400 ms,about 450 ms, about 500 ms, about 550 ms, about 600 ms, about 650 ms,about 700 ms, about 750 ms, about 800 ms, about 850 ms, about 900 ms,about 950 ms, ranges between such values, etc.), and thereafter notdelivered for between about 1 second and about 10 minutes (e.g., about 1second, about 5 seconds, about 10 seconds, about 15 seconds, about 30seconds, about 45 seconds, about 1 minute, about 2 minutes, about 3minutes, about 5 minutes, about 10 minutes, ranges between such values,etc.). An optimized duty cycle may, for example, reduce response time,increase battery life, patient comfort (reduce pain, cough, etc.), etc.The electrical pulses can also have a variety of waveforms, such as:square wave, biphasic square wave, sine wave, arbitrary definedwaveforms that are electrically safe, efficacious, and feasible, andcombinations thereof. The electrical pulses may be applied to multipletarget sites via multiple electrodes at least partially simultaneouslyand/or sequentially.

The methods of the present disclosure can include assigning a hierarchyof electrode configurations from which to deliver the one or moreelectrical pulses. The hierarchy can include two or more predeterminedpatterns and/or combinations of the plurality of electrodes to use indelivering the one or more electrical pulses. For example, the one ormore electrical pulses can be delivered using the hierarchy of electrodeconfigurations. A heart activity property sensed in response to the oneor more electrical pulses delivered using the hierarchy of electrodeconfigurations can be analyzed. Such an analysis can include, forexample, determining which of the hierarchy of electrode configurationsprovide the highest contractility or relative contractility of thepatient's heart. Based on this analysis, an electrode configuration canbe selected to use for delivering the one or more electrical pulsesthrough the catheter positioned in the pulmonary artery of the patient'sheart.

In some embodiments, a method can include assigning a hierarchy to oneor more properties of the one or more electrical pulses deliveredthrough the catheter positioned in the pulmonary artery of the heart.The hierarchy can include providing an order of which property (e.g.,electrode polarity, pulsing mode, pulse width, amplitude, frequency,phase, voltage, current, duration, inter-pulse interval, duty cycle,dwell time, sequence, wavelength, or waveform of the one or moreelectrical pulses) is to be changed and by how much, and for apredetermined number of electrical pulses delivered to the patient'sheart. The predetermined number of electrical pulses can be, forexample, 10 to 100 electrical pulses at a given property of thehierarchy. The one or more heart activity properties can be recorded forthe predetermined number of the one or more electrical pulses deliveredto the patient's heart for a given property of the one or moreelectrical pulses. The one or more heart activity properties sensed inresponse to the one or more electrical pulses can then be analyzed. Forexample, the recorded properties for each set of predetermined numbersof pulses can be analyzed against other sets of recorded propertiesand/or against predetermined standards for a given heart activityproperties and/or cardiac property (e.g., contractility). Based on thisanalysis, an electrode configuration can be selected to use fordelivering the one or more electrical pulses through the catheterpositioned in the pulmonary artery of the patient's heart. As anon-limiting example, a current of 1 mA can be applied to an electrodefor 50 electrical pulses, followed by the application of a current of 10mA to the electrode for 50 electrical pulses. The responses at 1 mA and10 mA can be compared. If 10 mA works better, a current of 20 mA can beapplied to the electrode for 50 electrical pulses, and the responses at10 mA and 20 mA can be compared. If 10 mA works better, 10 mA may beselected as the current for the method. A wide variety of selectionprocesses may be used, including but not limited to iterative methods(e.g., comprising making comparisons until a limit is found at which adifference is negligible) and brute force methods (e.g., measuringresponses and selecting one magnitude after completion of all responsesor until a certain value is achieved). This can be repeated for one ormore additional properties according to the hierarchy (e.g., currentfollowed by frequency). The selection process may be the same ordifferent for each member of the hierarchy.

In some embodiments, a first electrical signal of a series of electricalsignals is delivered (e.g., via a stimulation system such as thestimulation system 501) to an electrode in the pulmonary artery (e.g.,the right pulmonary artery, the left pulmonary artery, the pulmonarytrunk). After delivering the first electrical signal, a secondelectrical signal of the series of electrical signals is delivered(e.g., via the stimulation system) to the electrode. The secondelectrical signal differs from the first electrical signal by amagnitude of a first parameter of a plurality of parameters. Forexample, if the first parameter is current, the first electrical signalmay have a voltage such as 1 mA and the second electrical signal mayhave a different voltage such as 2 mA, while each of the otherparameters (e.g., polarity, pulse width, amplitude, frequency, voltage,duration, inter-pulse interval, dwell time, sequence, wavelength, andwaveform) are the same.

Sensor data indicative of one or more non-electrical heart activityproperties may be determined in response to delivering the series ofelectrical signals (e.g., via a sensor in the vasculature (e.g., as partof a same catheter that comprises the electrode, as part of a differentcatheter), via a sensor on a skin surface, combinations thereof, and thelike)). Electrical parameters to use for therapeutic modulation may beselected based at least partially on the sensor data. For example, theselected electrical parameters may comprise a selected magnitude of thefirst parameter. A therapeutic neuromodulation signal may be deliveredto the pulmonary artery using selected electrical parameters. Thetherapeutic neuromodulation signal may increase heart contractility(e.g., more than heart rate).

In some embodiments, a first series of electrical signals is delivered(e.g., via a stimulation system such as the stimulation system 501) toan electrode in the pulmonary artery (e.g., the right pulmonary artery,the left pulmonary artery, the pulmonary trunk). The first seriescomprises a first plurality of electrical signals. Each of the firstplurality of electrical signals comprises a plurality of parameters(e.g., polarity, pulsing mode, pulse width, amplitude, frequency, phase,voltage, current, duration, inter-pulse interval, duty cycle, dwelltime, sequence, wavelength, waveform, subsets thereof, or the like).Each of the first plurality of electrical signals of the first seriesonly differs from one another by a magnitude of a first parameter of theplurality of parameters (e.g., one of polarity, pulsing mode, pulsewidth, amplitude, frequency, phase, voltage, current, duration,inter-pulse interval, duty cycle, dwell time, sequence, wavelength, andwaveform changes in each of the first plurality of electrical signals).For example, if the first parameter is current, the first plurality ofelectrical signals of the first series may differ by having differentcurrents such as 1 mA, 2 mA, 3 mA, 4 mA, etc., while each of the otherparameters (e.g., polarity, pulsing mode, pulse width, amplitude,frequency, phase, voltage, duration, inter-pulse interval, duty cycle,dwell time, sequence, wavelength, and waveform) are the same.

After the first series of electrical signals is delivered to theelectrode, a second series of electrical signals can be delivered (e.g.,via the stimulation system) to the electrode. The second seriescomprises a second plurality of electrical signals. Each of the secondplurality of electrical signals comprises the plurality of parameters.Each of the second plurality of electrical signals of the second seriesonly differs from one another by a magnitude of a second parameter ofthe plurality of parameters different than the first parameter (e.g., adifferent one of polarity, pulsing mode, pulse width, amplitude,frequency, phase, voltage, current, duration, inter-pulse interval, dutycycle, dwell time, sequence, wavelength, and waveform changes in each ofthe second plurality of electrical signals). For example, if the firstparameter is current, the second parameter may be related to timing suchas frequency or duty cycle, For example, in the case of frequency, thesecond plurality of electrical signals of the second series may differby having different frequencies such as 1 Hz, 2 Hz, 3 Hz, 4 Hz, etc.,while each of the other parameters (e.g., current, polarity, pulsingmode, pulse width, amplitude, phase, voltage, duration, inter-pulseinterval, duty cycle, dwell time, sequence, wavelength, and waveform)are the same.

Sensor data indicative of one or more non-electrical heart activityproperties may be determined in response to delivering the first seriesof electrical signals and the second series of electrical signals (e.g.,via a sensor in the vasculature (e.g., as part of a same catheter thatcomprises the electrode, as part of a different catheter), via a sensoron a skin surface, combinations thereof, and the like)). Electricalparameters to use for therapeutic modulation may be selected based atleast partially on the sensor data. For example, the selected electricalparameters may comprise a selected magnitude of the first parameter anda selected magnitude of the second parameter. A therapeuticneuromodulation signal may be delivered to the pulmonary artery usingselected electrical parameters. The therapeutic neuromodulation signalmay increase heart contractility (e.g., more than heart rate).

Other series of electrical signals may be delivered to the electrode,for example only differing from one another by a magnitude of adifferent parameter of the plurality of parameters than the firstparameter and the second parameter. As many parameters as may be desiredto have a selected value may be calibrated or optimized. An order of theparameters may be based on a hierarchy (e.g., first select a current,then select a frequency, etc.).

A calibration or optimization process may be performed once (e.g., whena catheter 230, 330 is initially positioned) or a plurality of times.For example, the process may be repeated periodically or after a certainduration (e.g., once per hour, per 2 hours, per 4 hours, per 6 hours,per 8 hours, per 12 hours, per 18 hours, per 24 hours, per 36 hours, per2 days, per 60 hours, per 3 hours, etc.). In some implementations theprocess may be repeated upon detection of a change (e.g., by the sensor266, 366, 466). For example, if a heart activity property changes bymore than a certain percentage in a certain duration (e.g., ±10%, ±25%,±50%, etc. in <1 minute, <2 minutes, <5 minutes, etc.), that may beindicative that the catheter and/or sensor changed position or thatsomething else in the system or patient may have changed (e.g., patientcondition, physiological status, other therapy regiments, etc.).

Suitable examples of a stimulation system for use with the catheter inthe method of the present disclosure can be found in U.S. ProvisionalPatent Application No. 62/001,729, entitled “Catheter and CatheterSystem for Electrical Neuromodulation” and filed on May 22, 2014; PCTPatent Application No. PCT/US2015/179634, entitled “Catheter andCatheter System for Electrical Neuromodulation” and filed on May 21,2015; U.S. Provisional Patent Application No. 62/047,270, entitled“Catheter and Electrode Systems for Electrical Neuromodulation” andfiled on Sep. 8, 2014; PCT Patent Application No. PCT/US2015/047770,entitled “Catheter and Electrode Systems for Electrical Neuromodulation”and filed on Aug. 31, 2015; and U.S. patent application Ser. No.14/085,311, entitled “Methods and Systems for Treating Acute HeartFailure by Neuromodulation” and filed on Nov. 20, 2013.

For example, FIG. 5 provides an illustration of the stimulation systemsimilar to the stimulation system 11600 disclosed in U.S. ProvisionalPatent Application 62/001,729, entitled “Catheter and Catheter Systemfor Electrical Neuromodulation” and filed on May 22, 2014, which ishereby incorporated by reference in its entirety, and more specificallyfrom which FIG. 11 and page 41, line 5 to page 42, line 19 areincorporated herein by reference. As shown in FIG. 5, the stimulationsystem 501 includes an input/output connector 503 that can releasablyjoin the conductive elements of the catheter, conductive elements of asecond catheter, and/or sensors for sensing the one or more cardiacproperties from the skin surface of the patient, as discussed herein.The conductive elements and/or sensors may be permanently coupled to thestimulation system (e.g., not releasably coupled).

The input/output connector 503 is connected to an analog to digitalconverter 505. The output of the analog to digital converter 505 isconnected to a microprocessor 507 through a peripheral bus 509including, for example, address, data, and control lines. Themicroprocessor 507 can process the sensor data, when present, indifferent ways depending on the type of sensor in use. Themicroprocessor 507 can also control, as discussed herein, the pulsecontrol output generator 511 that delivers the electrical pulses to theone or more electrodes via the input/output connector 503 and/or housing523.

The properties of the electrical pulses can be controlled and adjusted,if desired, by instructions programmed in a memory 513 and executed by aprogrammable pulse generator 515. The memory 513 may comprise anon-transitory computer-readable medium. The memory 513 may include oneor more memory devices capable of storing data and allowing any storagelocation to be directly accessed by the microprocessor 507, such asrandom access memory (RAM), flash memory (e.g., non-volatile flashmemory), and the like. The stimulation system 501 may comprise a storagedevice, such as one or more hard disk drives or redundant arrays ofindependent disks (RAID), for storing an operating system and otherrelated software, and for storing application software programs, whichmay be the memory 513 or a different memory. The instructions in memory513 for the programmable pulse generator 515 can be set and/or modifiedbased on input from the sensors and the analysis of the one or moreheart activity properties via the microprocessor 507. The instructionsin memory 513 for the programmable pulse generator 515 can also be setand/or modified through inputs from a professional via an input 517connected through the peripheral bus 509. Examples of such an inputinclude a keyboard and/or a mouse (e.g., in conjunction with a displayscreen), a touch screen, etc. A wide variety of input/output (I/O)devices may be used with the stimulation system 501. Input devicesinclude, for example, keyboards, mice, trackpads, trackballs,microphones, and drawing tablets. Output devices include, for example,video displays, speakers, and printers. The I/O devices may becontrolled by an I/O controller. The I/O controller may control one ormore I/O devices. An I/O device may provide storage and/or aninstallation medium for the stimulation system 501. The stimulationsystem 501 may provide USB connections to receive handheld USB storagedevices. The stimulation system 501 optionally includes a communicationsport 519 that connects to the peripheral bus 509, where data and/orprogramming instructions can be received by the microprocessor 507and/or the memory 513.

Input from the input 517 (e.g., from a professional), the communicationsport 519, and/or from the one or more heart activity properties via themicroprocessor 507 can be used to change (e.g., adjust) the propertiesof the electrical pulses. The stimulation system 501 optionally includesa power source 521. The power source 521 can be a battery or a powersource supplied from an external power supply (e.g., an AC/DC powerconverter coupled to an AC source). The stimulation system 501optionally includes a housing 523.

The microprocessor 507 can execute one or more algorithms in order toprovide stimulation. The microprocessor 507 can also be controlled by aprofessional via the input 517 to initiate, terminate, and/or change(e.g., adjust) the properties of the electrical pulses. Themicroprocessor 507 can execute one or more algorithms to conduct theanalysis of the one or more heart activity properties sensed in responseto the one or more electrical pulses delivered using the hierarchy ofelectrode configurations and/or the hierarchy of each property of theone or more electrical pulses, for example to help identify an electrodeconfiguration and/or the property of the one or more electrical pulsesdelivered to the patient's heart. Such analysis and adjustments can bemade using process control logic (e.g., fuzzy logic, negative feedback,etc.) so as to maintain control of the pulse control output generator511.

The stimulation system 501 may comprise one or more additionalcomponents, for example a display device, a cache memory (e.g., incommunication with the microprocessor 507), logic circuitry, signalfilters, a secondary or backside bus, local buses, local interconnectbuses, and the like. The stimulation system 501 may support any suitableinstallation device, such as a CD-ROM drive, a CD-R/RW drive, a DVD-ROMdrive, tape drives of various formats, USB device, hard-drive,communication device to a connect to a server, or any other devicesuitable for installing software and programs. The stimulation system501 may include a network interface to interface to a Local Area Network(LAN), Wide Area Network (WAN), or the Internet through a variety ofconnections including, but not limited to, standard telephone lines, LANor WAN links, broadband connections, wireless connections (e.g.,Bluetooth, WiFi), combinations thereof, and the like. The networkinterface may comprise a built-in network adapter, network interfacecard, wireless network adapter, USB network adapter, modem, or any otherdevice suitable for interfacing the stimulation system 501 to any typeof network capable of communication and performing the operationsdescribed herein. In some embodiments, the stimulation system 501 maycomprise or be connected to multiple display devices, which may be ofthe same or different in type and/or form. As such, any of the I/Odevices and/or the I/O controller may comprise any type and/or form ofsuitable hardware, software, or combination of hardware and software tosupport, enable, or provide for the connection and use of multipledisplay devices by the stimulation system 501. The stimulation systemcan interface with any workstation, desktop computer, laptop or notebookcomputer, server, handheld computer, mobile telephone, any othercomputer, or other form of computing or telecommunications device thatis capable of communication and that has sufficient processor power andmemory capacity to perform the operations described herein and/or tocommunication with the stimulation system 501. The arrows shown in FIG.5 generally depict the flow of current and/or information, but currentand/or information may also flow in the opposite direction depending onthe hardware.

Analysis, determining, adjusting, and the like described herein may beclosed loop control or open loop control. For example, in closed loopcontrol, a stimulation system may analyze a heart activity property andadjust an electrical signal property without input from a user. Foranother example, in open loop control, a stimulation system may analyzea heart activity property and prompt action by a user to adjust anelectrical signal property, for example providing suggested adjustmentsor a number of adjustment options.

In some embodiments, a method of non-therapeutic calibration comprisespositioning an electrode in a pulmonary artery of a heart andpositioning a sensor in a right ventricle of the heart. The systemfurther comprises delivering, via a stimulation system, a first seriesof electrical signals to the electrode. The first series comprises afirst plurality of electrical signals. Each of the first plurality ofelectrical signals comprises a plurality of parameters. Each of thefirst plurality of electrical signals of the first series only differsfrom one another by a magnitude of a first parameter of the plurality ofparameters. The method further comprises, after delivering the firstseries of electrical signals to the electrode, delivering, via thestimulation system, a second series of electrical signals to theelectrode. The second series comprises a second plurality of electricalsignals. Each of the second plurality of electrical signals comprisesthe plurality of parameters. Each of the second plurality of electricalsignals of the second series only differs from one another by amagnitude of a second parameter of the plurality of parameters. Thesecond parameter is different than the first parameter. The methodfurther comprises determining, via the sensor, sensor data indicative ofone or more non-electrical heart activity properties in response todelivering the first series of electrical signals and the second seriesof electrical signals. The method further comprises determining atherapeutic neuromodulation signal to be delivered to the pulmonaryartery using selected electrical parameters. The selected electricalparameters comprise a selected magnitude of the first parameter and aselected magnitude of the second parameter. The selected magnitudes ofthe first and second parameters are based at least partially on thesensor data.

In some embodiments, a method of non-therapeutic calibration comprisesdelivering a first electrical signal of a series of electrical signalsto an electrode in a first anatomical location and, after delivering thefirst electrical signal, delivering a second electrical signal of theseries of electrical signals to the electrode. The second electricalsignal differs from the first electrical signal by a magnitude of afirst parameter of a plurality of parameters. The method furthercomprises sensing, via a sensor in a second anatomical locationdifferent than the first anatomical location, sensor data indicative ofone or more non-electrical heart activity properties in response to thedelivery of the series of electrical signals, and determining atherapeutic neuromodulation signal to be delivered to the firstanatomical location using selected electrical parameters. The selectedelectrical parameters comprise a selected magnitude of the firstparameter. The selected magnitude of the first parameter is based atleast partially on the sensor data.

The foregoing description and examples has been set forth merely toillustrate the disclosure and are not intended as being limiting. Eachof the disclosed aspects and embodiments of the present disclosure maybe considered individually or in combination with other aspects,embodiments, and variations of the disclosure. In addition, unlessotherwise specified, none of the steps of the methods of the presentdisclosure are confined to any particular order of performance.Modifications of the disclosed embodiments incorporating the spirit andsubstance of the disclosure may occur to persons skilled in the art andsuch modifications are within the scope of the present disclosure.Furthermore, all references cited herein are incorporated by referencein their entirety.

While the methods and devices described herein may be susceptible tovarious modifications and alternative forms, specific examples thereofhave been shown in the drawings and are herein described in detail. Itshould be understood, however, that the invention is not to be limitedto the particular forms or methods disclosed, but, to the contrary, theinvention is to cover all modifications, equivalents, and alternativesfalling within the spirit and scope of the various embodiments describedand the appended claims. Further, the disclosure herein of anyparticular feature, aspect, method, property, characteristic, quality,attribute, element, or the like in connection with an embodiment can beused in all other embodiments set forth herein. Any methods disclosedherein need not be performed in the order recited. Depending on theembodiment, one or more acts, events, or functions of any of thealgorithms, methods, or processes described herein can be performed in adifferent sequence, can be added, merged, or left out altogether (e.g.,not all described acts or events are necessary for the practice of thealgorithm). In some embodiments, acts or events can be performedconcurrently, e.g., through multi-threaded processing, interruptprocessing, or multiple processors or processor cores or on otherparallel architectures, rather than sequentially. Further, no element,feature, block, or step, or group of elements, features, blocks, orsteps, are necessary or indispensable to each embodiment. Additionally,all possible combinations, subcombinations, and rearrangements ofsystems, methods, features, elements, modules, blocks, and so forth arewithin the scope of this disclosure. The use of sequential, ortime-ordered language, such as “then,” “next,” “after,” “subsequently,”and the like, unless specifically stated otherwise, or otherwiseunderstood within the context as used, is generally intended tofacilitate the flow of the text and is not intended to limit thesequence of operations performed. Thus, some embodiments may beperformed using the sequence of operations described herein, while otherembodiments may be performed following a different sequence ofoperations.

The various illustrative logical blocks, modules, processes, methods,and algorithms described in connection with the embodiments disclosedherein can be implemented as electronic hardware, computer software, orcombinations of both. To clearly illustrate this interchangeability ofhardware and software, various illustrative components, blocks, modules,operations, and steps have been described above generally in terms oftheir functionality. Whether such functionality is implemented ashardware or software depends upon the particular application and designconstraints imposed on the overall system. The described functionalitycan be implemented in varying ways for each particular application, butsuch implementation decisions should not be interpreted as causing adeparture from the scope of the disclosure.

The various illustrative logical blocks and modules described inconnection with the embodiments disclosed herein can be implemented orperformed by a machine, such as a general purpose processor, a digitalsignal processor (DSP), an application specific integrated circuit(ASIC), a field programmable gate array (FPGA) or other programmablelogic device, discrete gate or transistor logic, discrete hardwarecomponents, or any combination thereof designed to perform the functionsdescribed herein. A general purpose processor can be a microprocessor,but in the alternative, the processor can be a controller,microcontroller, or state machine, combinations of the same, or thelike. A processor can also be implemented as a combination of computingdevices, e.g., a combination of a DSP and a microprocessor, a pluralityof microprocessors, one or more microprocessors in conjunction with aDSP core, or any other such configuration.

The blocks, operations, or steps of a method, process, or algorithmdescribed in connection with the embodiments disclosed herein can beembodied directly in hardware, in a software module executed by aprocessor, or in a combination of the two. A software module can residein RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory,registers, hard disk, a removable disk, an optical disc (e.g., CD-ROM orDVD), or any other form of volatile or non-volatile computer-readablestorage medium known in the art. A storage medium can be coupled to theprocessor such that the processor can read information from, and writeinformation to, the storage medium. In the alternative, the storagemedium can be integral to the processor. The processor and the storagemedium can reside in an ASIC. The ASIC can reside in a user terminal. Inthe alternative, the processor and the storage medium can reside asdiscrete components in a user terminal.

Conditional language used herein, such as, among others, “can,” “might,”“may,” “e.g.,” and the like, unless specifically stated otherwise, orotherwise understood within the context as used, is generally intendedto convey that some embodiments include, while other embodiments do notinclude, certain features, elements, and/or states. Thus, suchconditional language is not generally intended to imply that features,elements, blocks, and/or states are in any way required for one or moreembodiments or that one or more embodiments necessarily include logicfor deciding, with or without author input or prompting, whether thesefeatures, elements and/or states are included or are to be performed inany particular embodiment.

The methods disclosed herein may include certain actions taken by apractitioner; however, the methods can also include any third-partyinstruction of those actions, either expressly or by implication. Forexample, actions such as “positioning an electrode” include “instructingpositioning of an electrode.”

The ranges disclosed herein also encompass any and all overlap,sub-ranges, and combinations thereof. Language such as “up to,” “atleast,” “greater than,” “less than,” “between,” and the like includesthe number recited. Numbers preceded by a term such as “about” or“approximately” include the recited numbers and should be interpretedbased on the circumstances (e.g., as accurate as reasonably possibleunder the circumstances, for example ±5%, ±10%, ±15%, etc.). Forexample, “about 1 V” includes “1 V.” Phrases preceded by a term such as“substantially” include the recited phrase and should be interpretedbased on the circumstances (e.g., as much as reasonably possible underthe circumstances). For example, “substantially perpendicular” includes“perpendicular.” Unless stated otherwise, all measurements are atstandard conditions including temperature and pressure.

What is claimed is:
 1. A method of facilitating therapeuticneuromodulation of a heart of a patient, the method comprising:positioning an electrode in a pulmonary artery of a heart; positioning asensor in a right ventricle of the heart; delivering, via a stimulationsystem, a first series of electrical signals to the electrode, the firstseries comprising a first plurality of electrical signals, each of thefirst plurality of electrical signals comprising a plurality ofparameters, each of the first plurality of electrical signals of thefirst series only differing from one another by a magnitude of a firstparameter of the plurality of parameters; after delivering the firstseries of electrical signals to the electrode, delivering, via thestimulation system, a second series of electrical signals to theelectrode, the second series comprising a second plurality of electricalsignals, each of the second plurality of electrical signals comprisingthe plurality of parameters, each of the second plurality of electricalsignals of the second series only differing from one another by amagnitude of a second parameter of the plurality of parameters, thesecond parameter different than the first parameter; determining, viathe sensor, sensor data indicative of one or more non-electrical heartactivity properties in response to delivering the first series ofelectrical signals and the second series of electrical signals; anddelivering a therapeutic neuromodulation signal to the pulmonary arteryusing selected electrical parameters, wherein the selected electricalparameters comprise a selected magnitude of the first parameter and aselected magnitude of the second parameter, wherein the selectedmagnitudes of the first and second parameters are based at leastpartially on the sensor data, and wherein the therapeuticneuromodulation signal increases heart contractility more than heartrate.